Methods and devices for the sustained release of multiple drugs

ABSTRACT

The invention relates to an drug delivery device and a method for delivering multiple drugs over a prolonged period of time. The drug delivery device has two or more unitary segments comprising a drug-permeable polymeric substance, wherein at least one of the segments further comprises a pharmaceutically active agent. The invention also relates to a method for the treatment of a benign ovarian secretory disorder in a female mammal, a method of contraception, and a method of relieving the symptoms associated with menopausal, perimenopausal and post-menopausal periods in a woman.

RELATED APPLICATION(S)

This application is a divisional application of U.S. patent applicationSer. No. 10/835,414, filed on Apr. 29, 2004, entitled “Methods andDevices for the Sustained Release of Multiple Drugs,” which claims thebenefit of U.S. Provisional Application No. 60/466,318, filed on Apr.29, 2003 and U.S. Provisional Application No. 60/473,579, filed on May27, 2003. The entire teachings of the above applications areincorporated herein by reference.

FIELD

The invention relates to drug delivery devices for the simultaneousrelease of multiple drugs in a substantially constant ratio over aprolonged period of time. More specifically the invention relates tointravaginal devices and methods for contraception, hormone replacementtherapy, and therapeutic methods for the treatment of reproductiveconditions and disorders, such as benign ovarian secretory disorders.

BACKGROUND

The desirability of sustained release drug formulations has long been agoal in the pharmaceutical industry. Sustained release systems solvemany of the problems associated with conventional drug delivery systems,e.g., pills. For example in conventional drug delivery systemsadministration of the drug is given frequently and results in highvariability in circulating drug levels during the course of treatment.The concentration of the drug increases to therapeutic concentrationsafter administration, but in some instances the concentration risesabove the minimal therapeutic level reaching the toxic threshold. Aftera relatively short period of the drug concentration decreases viametabolization or excretion to levels that are no longer therapeutic.

In order to achieve constant levels of drugs and avoid theinefficiencies of the drug concentration peaks and valleys the drugsshould be released from a delivery system at a rate that does not changewith time (so called zero-order release). Preferably, the initial doseof a drug is the therapeutic dose, which is maintained by the deliverysystem. Examples of a current sustained drug delivery system include thereservoir systems which consist of tubes, fibers, laminates, ormicrospheres. In these systems, a drug reservoir is coated in arate-controlling membrane. Drug diffusion across the membrane is ratelimiting and is constant (zero order) as long as the membrane'spermeability does not change and as long as the concentration of drug inthe reservoir is constant.

In matrix systems drugs are dispersed through a matrix and are releasedas the drugs dissolve and diffuse through the matrix. A drug is releasedfrom the outer surface of the matrix first, this layer becomes depleted,and a drug that is released from further within the core of the devicemust then diffuse through the depleted matrix. The net result is thatthe release rate slows down and thus it is very difficult to maintainconstant and consistent release. Other types of devices are polymericdevices that contain a polymeric material that is permeable to thepassage of the drug. Although it is possible to choose from among alarge variety of polymeric materials, in practice only a small number ofpolymers have been shown to function satisfactorily as arelease-determining outer layer of the reservoir. Sustained releasesystems that release two or more active substances over a prolongedperiod of time are extremely useful for certain applications, forexample, the in fields of contraception and hormone replacement therapy.

Ring-shaped vaginal drug delivery devices (“vaginal rings”) are wellknown in the art. Such devices are designed to deliver a relativelyconstant dose of drug to the vagina, usually over a period of weeks tomonths. Typically, they are made of a silicone elastomer and contain adrug released by diffusion though the elastomer. Vaginal rings have beendeveloped for delivering steroids to treat post-menopausal vaginalconditions, as well as for contraception and hormone replacementtherapy. Women generally prefer vaginal rings to oral delivery forseveral reasons, particularly their convenience, privacy, long-termdelivery capacity, and effectiveness. Vaginal rings provide a regulateddose of drug with minimal involvement or attention by the user. Theyalso avoid the first pass of orally administered drugs through theliver, where appreciable portions of the daily dosage of some orallyadministered steroids are degraded.

U.S. Pat. No. 4,292,965 (Nash et al.) and U.S. Pat. No. 4,822,616(Zimmermann et al.) disclose two-layered vaginal rings. The ringscomprise an inner drug-free supporting ring, a middle layer comprising adrug, and an outer drug-free layer. All three layers preferably comprisea silicone elastomer. However, the use of silicone elastomers is nowgenerally considered to be unsafe, and is no longer the material ofchoice.

In addition to single drug delivery, vaginal rings have been developedfor simultaneous release of multiple drugs over a prolonged period oftime. For example, U.S. Pat. No. 3,995,633 (Gougeon) and U.S. Pat. No.3,995,634 (Drobish) disclose vaginal rings comprising separatereservoirs containing different active substances, wherein thereservoirs are arranged in holders. U.S. Pat. No. 4,237,885 (Wong etal.) also discloses a multi-reservoir device, in which spacers are usedto divide a tube or coil into portions, wherein each portion is filledwith a different active substance in a silicone fluid and the two endsof the tube are subsequently connected to form a ring. PatentPublication WO 97/02015 (Groenewegen et al.) discloses a two-compartmentdevice, wherein one compartment has a core, a medicated middle layer anda non-medicated outer layer, and a second compartment having a medicatedcore and a non-medicated outer layer. However, the active substances inthese multi-compartment or multi-reservoir devices typically diffusethrough the walls of the tubes, thus allowing drug interactions,particularly during prolonged storage. Interactions between the drugsoften results in degradation or inactivation of at least one of thedrugs, and thus variations in the pre-set fixed release ratio betweenthe drugs over time.

The device described in U.S. Pat. No. 4,596,576 (de Nijs) was designedto overcome the diffusion problem associated with multi-compartmentdevices. de Nijs discloses a two-compartment vaginal ring wherein eachcompartment comprises a reservoir filled with a different activesubstance. However, to prevent diffusion and maintain a constant releaseratio between the various active substances over time, the drugcompartments are separated by impermeable inert stoppers, formed ofglass, gold or silver. Although the stoppers effectively preventdiffusion of active substance between reservoirs, the device iscomplicated and expensive to manufacture.

The device described in U.S. Pat. No. 5,989,581 (Groenewegen) was alsodesigned to overcome the diffusion problems associated with existingdelivery systems, as well as to provide a less complicated and cheaperdevice for intravaginal delivery of multiple active substances. Thepatent discloses a ring-shaped drug delivery system for the simultaneousrelease of a progestogenic steroid compound and an estrogenic steroidcompound, reportedly in a fixed ratio over a prolonged period of time.The drug delivery system has a compartment comprising a thermoplasticpolymer core containing the mixture of the progestogenic and estrogeniccompounds and a thermoplastic polymer skin. However, like other knownvaginal devices, the Groenewegen device suffers from its own inherentlimitations. In general, the release per unit time of a drug isdetermined by the solubility of the active substance in the outer layer(wall) of polymeric material and by the diffusion coefficient of theactive substance in the wall. Thus, the choice of the outer layermaterial of the reservoir largely determines the release ratio of theactive substances contained in the reservoir. Unfortunately, only a fewpolymers are capable of functioning satisfactorily as arelease-determining outer layer of the reservoir. Finding theappropriate polymer for a particular drug or drug combination can bedifficult. Moreover, the reservoir material must be capable of taking upa large amount of the active substance or substances in order to providean adequate supply of the substances to the outer wall. Meeting thesechallenges is problematic, if not impossible, and must be addressed foreach new drug or drug combination.

An intravaginal drug delivery device which can release two or moreactive substances in a substantially constant ratio to one another overa lengthy period of time would be extremely useful for certainapplications. For example, in the field of contraception and in thefield of hormone replacement therapy, extensive use is made of thesimultaneous administration of an agent having a progestogenic activityand an agent having an estrogenic activity, preferably in asubstantially constant ratio.

Drug delivery systems and methods for contraception and for treatingfemale reproductive disorders using combination therapy have beendeveloped. For example, U.S. Pat. No. 4,762,717 (Crowley, Jr.) disclosesa delivery system for the continuous delivery of LHRH compositions incombination with sex steroid for use as a contraceptive. U.S. Pat. No.5,130,137 (Crowley, Jr.) discloses a similar delivery system for thetreatment of benign ovarian secretory disorders.

Despite these significant advances in the field, a need exists for animproved method for contraception and treatment of female reproductiveconditions and disorders, such as treatment of benign ovarian secretorydisorders and post-menopausal hormone replacement therapy. Inparticular, a method that uses a hormone replacement steroid and/or aLHRH and/or its analogues (either agonists and/or antagonists), and thatcan be administered in a safe, physiologic, and convenient manner, wouldbe highly desirable. Moreover, a need exists for an improved drugdelivery system for the simultaneous release of LHRH and sex steroids orsex steroid modulators, particularly a system which releases the LHRHand steroids in a substantially constant ratio over a prolonged periodof time, and which is easy and inexpensive to manufacture.

Additionally, constant and reliable delivery of drugs or combinations ofdrugs over long periods of time would be useful in a wide variety ofapplications, including treatment or prevention of AIDS/HIV,atherosclerosis, various cancers, cardiovascular diseases, hypertension,toxemia of pregnancy, seizures, degenerative neurological disorders,diabetes, hematological disorders, addictions, and obesity and eatingdisorders, to name a few. Unfortunately, in addition to not alwaysproviding satisfactory release, release ratio, or release term in somecases, all currently available intravaginal drug delivery devices sufferfrom being relatively complicated, making them expensive to manufacture.Thus, a need exists for an improved drug delivery device for thesimultaneous release of multiple drugs, particularly a device whichreleases the drugs in a substantially constant ratio over a prolongedperiod of time, and which is easy and inexpensive to manufacture.

SUMMARY

It is an object of the present invention to provide a drug deliverydevice for the sustained release of multiple drugs over a prolongedperiod of time. Additionally, the present invention also provides for aless expensive and easier to produce device than currently availabledevices. It is also an object of the invention to provide a method oftreating disease with the device, particularly benign ovarian secretorydisorders. It is also an object of the invention to administer multipledrugs for use in contraception and hormone replacement therapy.

In a first aspect, the present invention relates to a drug deliverydevice comprising two or more unitary segments. Each segment comprises adrug-permeable polymeric substance, and at least one segment comprises amixture of the drug-permeable polymeric substance and a drug. Two ormore segments may each contain a drug, preferably a different drug ineach segment. The drug-permeable polymeric substance may be athermoplastic polymer, such as an ethylene-vinyl acetate copolymer. Atleast one end of a segment may be attached to the end of another unitarysegment by a coupling means, such as an adhesive material or byannealing the ends of the segments to same or different thermoplasticpolymers. The drug delivery device may be in the shape of a ring, awafer, or a suppository, and may be suitable for use as a vaginal ring.The drug delivery device may have an overall diameter of from 40 mm to80 mm, and a cross-sectional diameter of from 2 mm to 12 mm. The drug tobe delivered may be a hormone replacement steroid or a contraceptiveagent, for example an estrogenic compound, a progestational compound,and/or a gonadotropin releasing hormone or its peptide or non-peptideagonists or antagonist analogues. The drug may also be an interferon,anti-angiogenesis factors, growth factors, hormones, enzymes,transferases, hydrolases, lysases, isomerases, proteases, ligases andoxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs,antibiotics, growth hormone, polysaccharides, antigens, and antibodies.

In another aspect, the invention relates to a drug delivery system forthe simultaneous release of two or more drugs. The drug delivery systemcomprises two or more unitary segments, wherein at least two of thesegments comprise a mixture of a drug-permeable polymeric substance anda drug. Moreover, at least two of the segments may comprise a differentdrug, and the drug-permeable polymeric substance may be a thermoplasticpolymer, such has an ethylene-vinyl acetate copolymer. The drug may be ahormone replacement steroid or a contraceptive agent, for example anestrogenic compound, a progestational compound, and/or a gonadotropinreleasing hormone or its agonistic or antagonistic analogues. The drugmay also be an interferon, anti-angiogenesis factors, growth factors,hormones, enzymes, transferases, hydrolases, lysases, isomerases,proteases, ligases and oxidoreductases, enzyme inhibitors, steroids,anti-cancer drugs, antibiotics, growth hormone, polysaccharides,antigens, and antibodies.

In still a further aspect, the invention relates to a method fordelivering a drug to a female mammal. The method comprises preparing adrug delivery device comprising two or more unitary segments, whereineach segment comprises a drug-permeable polymeric substance, and whereinat least one segment comprises a mixture of the drug-permeable polymericsubstance and a drug. The drug delivery device is then positioned in thevaginal tract of the female mammal, and maintained in the vaginal tractfor a period of time sufficient to deliver an effective amount of thedrug to the female mammal. The drug-permeable polymeric substance may bea thermoplastic polymer, such as an ethylene-vinyl acetate copolymer.The drug may be a hormone replacement steroid or a contraceptive agent,for example an estrogenic compound, a progestational compound, and/or agonadotropin releasing hormone. The drug may also be interferon,anti-angiogenesis factors, growth factors, hormones, enzymes,transferases, hydrolases, lysases, isomerases, proteases, ligases andoxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs,antibiotics, growth hormone, polysaccharides, antigens, and antibodies.In yet another aspect, the invention relates to a method of making aring-shaped drug delivery device. The method comprises mixing a firstdrug-permeable polymeric substance with a first drug to form a firstpolymeric mixture, molding the first polymeric mixture to form a firstring, and cutting the first ring to form two or more first unitarysegments. The method is then repeated with a second drug-permeablepolymeric substance and a second drug to form a second unitary segment.The first and second drug-permeable polymeric substances may be the sameor different. An end of a first segment is then connected to an end of asecond segment to form a ring-shaped drug delivery device. The first andsecond drug-permeable polymeric substances may be a thermoplasticpolymer, such as an ethylene-vinyl acetate copolymer. The foregoingmethod may be repeated with a third drug-permeable polymeric substanceand a third drug to form a third unitary segment. Additional segmentsmay be prepared by the same method. The connection of the segments maybe performed using an adhesive material or by annealing the ends of thesegments with the same or a different thermoplastic polymer. In analternate embodiment, the ring-shaped drug delivery device is formed bypreparing individual segments, instead of rings, and connecting the endsof the segments to form the ring-shaped drug delivery device.

In another aspect the invention relates a method of making a ring-shapeddrug delivery device. The method comprises mixing a first drug-permeablepolymeric substance with a first drug to form a first polymeric mixture,injecting the first polymeric mixture into a mold to form a firstunitary segment. The method is then repeated with a seconddrug-permeable polymeric substance and a second drug to form a secondunitary segment and thus forming the drug delivery device. The first andsecond drug-permeable polymeric substances may be the same or different.The first and second drug-permeable polymeric substances may be athermoplastic polymer, such as an ethylene-vinyl acetate copolymer. Theforegoing method may be repeated with a third drug-permeable polymericsubstance and a third drug to form a third unitary segment. Additionalsegments may be prepared by the same method.

In another aspect, the present invention relates to a method for thetreatment of a benign ovarian secretory disorder in a female mammal,such as polycystic ovarian disease (PCOD). The method comprisesproviding a drug delivery device comprising at least two segments,wherein the first segment comprises a drug-permeable polymeric substanceand a luteinizing hormone releasing hormone (LHRH) or one of itsagonistic or antagonistic analogues or a small molecular weight mimicthat either binds to the GnRH receptor or blocks its subsequentmechanism of action, and wherein the second segment comprises thedrug-permeable polymeric substance and an estrogenic steroid. The drugdelivery device is then inserted into the vagina of the female mammal torelease a therapeutically effective amount of the LHRH and an effectiveamount of the estrogenic steroid or estrogen receptor modulator (toavoid the metabolic consequences of the castrational state induced bythe LHRH). The drug delivery device may further comprise a thirdsegment, which comprises the drug-permeable polymeric substance and aprogestational steroid or a progestin receptor modulator, and whichreleases an effective amount of the progestational steroid. Thedrug-permeable polymeric substance may be a thermoplastic polymer, suchas an ethylene-vinyl acetate copolymer. The drug delivery device may bein the shape of a ring, a wafer, or a suppository, preferably a ringshape. The benign ovarian secretory disorder may be polycystic ovariandisease. The benign ovarian secretory disorder may be characterized byexcessive ovarian androgen secretion, excessive ovarian estrogensecretion, hyperthecosis, hirsutism, dysfunctional uterine bleeding,amenorrhea, or anestrus. The female mammal may be a human female. Theestrogen steroid may be estradiol, estradiol benzoate, estradiolcypionate, estradiol dipropionate, estradiol enanthate, conjugatedequine estrogen, estriol, estrone, estrone sulfate, ethinyl estradiol,estrofurate, quinestrol or mestranol. The estrogen steroid may also be aselective estrogen receptor modulators such as tamoxifen, raloxifene,clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI 182,780,ICI 164,384, diethylstilbesterol, genistein, nafoxidine, moxestrol,19-nor-progesterone derivatives, or 19-nor-testosterone derivatives. Theprogestation steroid may be progesterone, 17-hydroxy progesteronederivatives, 19-nor-testosterone derivatives, 19-nor-progesteronederivatives norethindrone, norethindrone acetate, norethynodrel,norgestrel, norgestimate, ethynodiol diacetate, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone levo-norgestrel, di-norgestrel,cyproterone acetate, gestodene, desogestrol, dydrogesterone, ethynodioldiacetate, medroxyprogesterone acetate, megestrol acetate,phytoprogestins, or an animal-derived progestin or metabolic derivativesthereof. The progestational steroid may also be a selective progestinreceptor modulator such as RU486, CDB2914, a 19-nor-progesteronederivative, a 19-nor-testosterone derivative, a6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivative, a5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline derivative, a 5-alkyl1,2-dihydrochomeno[3,4-f]quinoline derivative, or a6-thiophenehydroquinoline derivative.

In another aspect, the invention relates to preventing pregnancy in afemale mammal. The method comprises providing a drug delivery devicecomprising: (1) a first segment comprising a drug-permeable polymericsubstance and a luteinizing hormone releasing hormone (LHRH) or one ofits agonistic or antagonistic analogues or a small molecular weightmimic that either binds to the GnRH receptor or blocks its subsequentmechanism of action, (2) a second segment comprising the drug-permeablepolymeric substance and an estrogenic steroid or selective estrogenreceptor modulator (SERM), and (3) a third segment comprising thedrug-permeable polymeric substance and a progestational steroid orselective progestin receptor modulator (SPRM). The drug delivery deviceis then inserted into the vagina of the mammal to release atherapeutically effective amount of the LHRH, an effective amount of theestrogenic steroid or selective estrogen receptor modulator (SERM), andan effective amount of the progestational steroid or SPRM to the femalemammal. The drug-permeable polymeric substance may be a thermoplasticpolymer, such as an ethylene-vinyl acetate copolymer. The drug deliverydevice may be in the shape of a ring, a wafer, or a suppository,preferably a ring shape.

In yet another aspect, the invention relates to a method of treating adecrease in estrogen secretion in a woman exhibiting symptoms of acessation of cyclical ovulation and/or the peri-menopause. In oneembodiment, the method comprises providing a drug delivery devicecomprising: (1) a first segment comprising a drug-permeable polymericsubstance and a luteinizing hormone releasing hormone (LHRH) or one ofits agonistic or antagonistic analogues or a small molecular weightmimic that either binds to the GnRH receptor or blocks its subsequentmechanism of action, (2) a second segment comprising the drug-permeablepolymeric substance and a hormone replacement steroid, such as anestrogenic steroid or selective estrogen receptor modulator (SERM), and(3) a third segment comprising the drug-permeable polymeric substanceand a progestational steroid or selective progestin receptor modulator(SPRM). In an optional embodiment, the drug delivery device furthercomprises a fourth segment, which comprises a drug-permeable polymericsubstance and an androgen or a selective androgen receptor modulator(SARM). The drug delivery device is then inserted into the vagina of thewoman to release effective amounts of the LHRH, sex steroids and/or sexsteroid modulators. The estrogen component of the hormone replacementsteroid may be an estrogenic steroid, such as a naturally occurringestrogen or a synthetic estrogen. The estrogenic steroid may beestradiol, estradiol benzoate, estradiol cypionate, estradioldipropionate, estradiol enanthate, conjugated equine estrogen, estriol,estrone, estrone sulfate, ethinyl estradiol, estrofurate, quinestrol ormestranol or other estrogenic steroids.

In still another aspect, the invention relates to a method of treating adecrease in estrogen secretion in a woman exhibiting symptoms of acessation of cyclical ovulation and/or the menopause. The methodcomprises providing a drug delivery device comprising at least twosegments, wherein the first segment comprises a drug-permeable polymericsubstance and a hormone replacement steroid, such as an estrogenicsteroid or selective estrogen receptor modulator (SERM), and wherein thesecond segment comprises a drug-permeable polymeric substance and aprogestational steroid or a selective progestin receptor modulator(SPRM). In an optional embodiment, the drug delivery device furthercomprises a third segment, which comprises a drug-permeable polymericsubstance and an androgen or a selective androgen receptor modulator(SARM). The drug delivery device is then inserted into the vagina of thewoman to release an effective amount of the hormone replacement steroid.The estrogen component of the hormone replacement steroid may be anestrogenic steroid, such as a naturally occurring estrogen or asynthetic estrogen, such as those described above.

In still a further aspect, the invention relates to a method forrelieving the symptoms and signs associated with menopausal,perimenopausal and post-menopausal periods in a woman having theseperiods and in need of estrogen therapy. The method comprises providinga drug delivery device having a first segment and a second segment,wherein the first segment comprises a drug-permeable polymeric substanceand an estrogenic steroid. The drug delivery device in then insertedinto the vagina of the woman to release an effective amount of theestrogenic steroid. The drug-permeable polymeric substance may be athermoplastic polymer, such as an ethylene-vinyl acetate copolymer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a ring-shaped intravaginal drug delivery device consistingof two segments 12 and 13, which are connected to each other by acoupling means;

FIG. 2 illustrates the serum level (ng/ml) of gonadotropin releasinghormone (GnRH) in Rhesus monkeys following vaginal administration of acomposition comprising GnRH and a commercially available hydrogel(Replenz®);

FIG. 3 illustrates the in vitro zero order release kinetics of estradiol(circles) and progesterone (squares) from an EVA-based intravaginaldelivery device of the invention;

FIG. 4 illustrates the in vitro zero order release kinetics of naturalGnRH from an EVA-based intravaginal delivery device of the invention;

FIG. 5 illustrates the bi-phasic release kinetics of estradiol (circles)and progesterone (squares) from EVA-based delivery devices;

FIG. 6 illustrates the effect of cellulosics on the release kinetics ofprogesterone from an EVA-based delivery device, where highconcentrations of ethocel are represented by diamonds and lowconcentrations of ethocel are represented by squares;

FIG. 7 illustrates the bi-phasic release kinetics of estradiol (circles)and progesterone (squares) from a single EVA-based delivery device;

FIG. 8 illustrates the pharmacokinetics of intravaginally administeredGnRH in Rhesus monkeys and the corresponding effect on endogenous levelsof luteinizing hormone (LH, diamonds); and

FIG. 9 shows a ring-shaped multiple port mold consisting of a Portal No.1, Portal No. 2, Portal No. 3, and Portal No. 4.

DETAILED DESCRIPTION

The present invention relates to a drug delivery device, a method fordelivering a drug to a female mammal, a method of making a ring-shapeddrug delivery device, methods for the treatment of a benign ovariansecretory disorder, methods of contraception and methods for hormonereplacement therapy.

The drug delivery device, which comprises a drug-permeable polymericsubstance, has at least two unitary segments. The segments arepreferably joined end to end to form a ring shape. At least one of thesegments comprises a mixture of the drug-permeable polymeric substanceand a drug, wherein the drug is substantially uniformly dispersedthroughout the segment. The invention further relates to a drug deliverysystem for the simultaneous release of a plurality of drugs, wherein thesystem releases the drugs in a substantially constant ratio over aprolonged period of time. The method of delivering the drug orcombination of drugs to the female mammal comprises the steps ofpreparing a drug delivery device having two or more unitary segments,positioning the device in the vaginal tract of the female mammal, andmaintaining the device in the vaginal tract for a period of timesufficient to deliver a pharmaceutically effective amount of the drug(s)to the female mammal.

As stated above, the drug delivery device, which comprises adrug-permeable polymeric substance, has at least two unitary segments.The device may be in any physiologically acceptable shape, such as aring, a wafer, or a suppository. In one embodiment, the segments arejoined end to end to form a ring shape. At least one of the segmentscomprises a mixture of the drug-permeable polymeric substance and adrug, wherein the drug is substantially uniformly dispersed throughoutthe segment. Because of its unique design, the drug delivery device ofthe present invention provides simultaneous release of a plurality ofdrugs, in a substantially constant ratio over a prolonged period oftime.

The drug delivery device can be easily manufactured, and provides forthe reliable and predictable release of the drug or drug combination. Incontrast to known intravaginal drug delivery devices comprising adrug-containing fluid core or reservoir, the solid thermoplastic devicesused in the methods of the present invention are not susceptible torupture and the consequent leakage of drug-containing fluid. Moreover,unlike existing devices comprising multiple layers or compartments, thedevices described herein can be easily and cheaply manufactured usingconventional extrusion technology.

The thermoplastic polymer used in the manufacture of the device may beany thermoplastic polymer or elastomer material suitable forpharmaceutical use, such as polysiloxanes, polyurethane, polyethylene,ethylene-vinyl acetate copolymers, cellulose, copolymers of polystyrene,polyacrylates and various types of polyamides and polyesters. Theethylene-vinyl acetate copolymer (EVA) is highly preferred due to itsexcellent mechanical and physical properties (e.g., solubility of thedrug in the material). The EVA material can be any commerciallyavailable ethylene-vinyl acetate copolymer, such as the productsavailable under the names Elvax®, Evatane®, Lupolen®, Movriton®,Ultrathene® and Vestypar®.

The intravaginal drug delivery device used in the methods of the presentinvention can be manufactured in any size as required. In the case ofhuman use, the ring-shaped device has an outer diameter from about 40 mmto about 80 mm, and preferably between 50 mm and 60 mm; thecross-sectional diameter is preferably between about 1 mm and about 12mm, and preferably between 2 and 6 mm.

The present invention also relates to methods for the treatment of abenign ovarian secretory disorder and for preventing pregnancy in afemale mammal, as well as methods for treating a decrease in estrogensecretion in a woman exhibiting symptoms of a cessation of cyclicalovulation and for relieving the symptoms and signs associated withmenopausal, perimenopausal and post-menopausal periods in a woman. Themethods comprise providing a drug delivery device having two or moreunitary segments, wherein at least one of the segments comprises adrug-permeable polymeric substance and a drug. The choice of drug(s)will depend on the particular application or indication being treated.For example, for contraceptive uses and the treatment of a benignovarian secretory disorder, the drugs are a luteinizing hormonereleasing hormone (LHRH) and an estrogenic steroid and sequentialprogesterone/progestine; for contraceptive purposes, the drugs are LHRH,an estrogenic steroid, and progestational steroid; and, for treating adecrease in estrogen secretion, the drug is a hormone replacementsteroid, such as an estrogenic steroid. An estrogenic steroid is alsothe drug used in methods for relieving the symptoms and signs associatedwith menopause. Similarly, progesterone can be used in methods forrelieving the symptoms and signs associated with menopause. The drugdelivery device is then inserted into the vagina of the female mammal,such as a human female, to release an effective amount(s) of thedrug(s). The drug-permeable polymeric substance may be a thermoplasticpolymer, such as an ethylene-vinyl acetate copolymer. The drug deliverydevice may be in the shape of a ring, a wafer, or a suppository,preferably a ring shape.

The following detailed description discloses how to practice the methodsof the present invention. It also describes how to make and use theintravaginal drug delivery device to deliver a pharmaceuticallyeffective amount of a drug to a female mammal.

I. DEFINITIONS

For convenience, the meaning of certain terms and phrases used in thespecification, examples, and appended claims are provided below.

As used herein, the terms “unitary segment” or “segment” refer to asolid material having a substantially uniform or homogenous compositionthroughout. The terms “segment” and “unitary segment” specificallyexclude vaginal rings or portions thereof comprising a core or reservoirand an inner and/or outer layer of material, such as a skin, wall,membrane, coating, or polymeric layer or layers.

As used herein, the terms “unitary cylindrical segment” and “unitarycylindrical rod” refer to a solid cylinder or rod-shaped material havinga substantially uniform or homogenous composition throughout. The terms“segment” and “unitary cylindrical rod” specifically exclude vaginalrings or portions thereof comprising a core or reservoir and an innerand/or outer layer of material, such as a skin, wall, membrane, coating,or polymeric layer or layers.

As used herein, the term “drug-permeable” refers to a polymeric materialthrough which a drug can diffuse and thus be absorbed for local and/orsystemic effects in a mammal. The term “non-absorbable” means there isno absorption of the polymeric material in the vaginal tract of thefemale mammal being treated. The term “non-erodible” means that thepolymeric material does not erode in the vaginal tract of the femalemammal. The term “non-degradable” means that the polymeric material doesnot degrade or break down in vivo. The term “compatible” meanscompatible both with the environment of the vaginal tract in that thereis no breakdown of the tensile nature or structural integrity of thedevice due to the contents of the vagina. Likewise there is nodeleterious action on the sensitive tissue in the area of placement inthe vaginal tract. Widely varying types of polymeric material aresuitable in providing these non-toxic, drug-permeable properties, forexample polysiloxanes, polyurethane, polyethylene, ethylene-vinylacetate copolymers, cellulose, copolymers of polystyrene, polyacrylatesand various types of polyamides and polyesters. The above-mentionedpolymers can be used in a porous or microporous form. The term“thermoplastic polymer” refers to a polymeric material which is capableof being softened by heating and hardened by cooling through atemperature range characteristic of the polymer, and in the softenedstate can be shaped by flow into devices by molding or extrusion.

As used herein, the term “coupling means” refers to a method, mechanism,material or device for joining or connecting the ends of two unitarysegments or unitary cylindrical rods to each other. The term “adhesivematerial,” as used herein refers to an inert bonding agent, glue, orother substance having sufficient adhesive properties to bind the endsof the segments. The adhesive material can be, for example, a medicalgrade silicone adhesive.

As used herein, the terms “patient” and “female mammal” are usedinterchangeably to refer to a human or other animal in which it isdesired to provide a medical treatment or contraceptive agent.

By “simulating or inducing the follicular or luteal phase of themenstrual cycle” is meant to simulate or induce the sex steroid hormonemilieu in the patient so as to provide such patient with levels of sexsteroid hormones that approximate the endocrine environment of a normalfollicular or luteal phase.

As used herein, “benign ovarian secretory disorders” refers to any of avariety of benign conditions in which suppression of ovarian function isimportant. These conditions largely center around benign secretorydisorders of the ovaries such as (a) polycystic ovarian disease andhyperandrogenic hirsutism, and/or (b) excessive ovarian sex steroidsecretion of androgens, estrogens or progestins. Benign ovariansecretory disorders may be characterized, for example, by hyperthecosis,hirsutism, dysfunctional uterine bleeding, amenorrhea, anestrus, oroligomenorrhea.

By “excessive” ovarian sex steroid secretion of androgens, estrogens orprogestins is meant secretion of androgens, estrogens or progestins inamounts such that the ratios of the androgens, estrogens or progestinsin the serum of a patient are abnormal when compared to normal levels ofsuch androgens, estrogens or progestins for the female mammal.Therefore, “excessive” estrogen secretion is meant to encompassconditions wherein the ovaries secrete estrogen levels that do notconform to the normal levels encountered in female reproductionphysiology such as the normal menstrual cycle; “excessive” progestinsecretion is meant to encompass conditions wherein the ovaries secretetoo much progestin, e.g., levels excessive or inappropriate for normalphysiologic levels in normal women; and, “excessive” androgen secretionis meant to encompass conditions wherein the ovaries secrete too muchandrogen, e.g., levels above those encountered in normal femalephysiology.

As used herein, “LHRH” and “LHRH composition” refer to luteinizinghormone releasing hormone (LHRH), LHRH analogues, LHRH agonists and LHRHantagonists analogues (peptide and/or non-peptide in nature), and/or anycompound (peptide or non-peptide) that can bind to the LHRH receptorand/or can produce hypogonadotropic hypogonadism in a mammal, such as ahuman. The LHRH that may be used in this invention are physiologicallyactive peptides or non-peptide analogues capable of binding to the LHRHreceptor and are gonadotropin secretory inhibitors orgonadotropin-receptor-effect blockers. LHRH is characterized as adecapeptide having the following structure:

SEQ ID NO:1 p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂

As used herein, the terms “LHRH agonist” and “LHRH antagonist” refer tosuch physiologically active peptides or non-peptide analogues whichrespectively enhance or inhibit the biological activity of LHRH. Forexample, LHRH agonists useful in the methods of the invention include,but are not limited to, Cystorelin (Hoechst), Gonadorelin (Ayerst),Zoladex (ICI), Buserelin (Boechst), Leuprolide (Abbott/Takeda),Decapeptyl (Debiopharm, Ipsen/Beaufour), Nafarelin (Syntex), Lutrelin(Wyeth) and Histrelin (Ortho). LHRH, LHRH analogues, LHRH agonists andLHRH antagonists are well known in the art and are described in numerouspatents, including the following patents: U.S. Pat. Nos. 4,705,778,4,690,916, 4,530,920; 4,481,190; 4,419,347; 4,341,767; 4,318,905;4,234,571; 4,386,074; 4,244,946; 4,218,439; 4,215,038; 4,072,668;4,431,635; 4,317,815; 4,010,125; 4,504,414; 4,493,934; 4,377,515;4,504,414; 4,338,305; 4,089,946; 4,111,923; 4,512,923; 4,008,209; and4,010,149, all incorporated herein by reference. The LHRH compositionsdescribed in the above patents may be used in the methods of thisinvention.

As used herein, the terms “estrogenic steroid” and “estrogen” are usedinterchangeably to refer to an agent, natural or synthetic, that exertsbiological effects characteristic of estrogenic hormones such asestradiol. As used herein, the terms “estrogenic steroid” and “estrogen”also encompasses “conjugated estrogens,” which are an amorphouspreparation of naturally occurring, water-soluble, conjugated forms ofmixed estrogens that typically are obtained from the urine of pregnantmares (e.g., sodium estrone sulfate). Also included are “esterifiedestrogens,” which are a mixture of the sodium salts of sulfate esters orglucanoride of sulfate conjugates of estrogenic substances. Examples ofsuitable estrogens include, without limitation, estradiol valerate,estradiol benzoate, 17-β estradiol, estradiol cypionate, estrone,piperazine estrone sulfate, estriol, ethyl estradiol, polyestradiolphosphate, estrone potassium sulfate, benzestrol, chlorotrianisene,methallenestril, dienestrol, diethylstilbestrol diphosphate, mestranol,diethylstilbestrol (DES), quinestranol, phytoestrogens, animal-derivedestrogens (e.g., equine estrogens), and metabolic derivatives ofanimal-derived estrogens. These also include any steroid ornon-steroidal compound that binds either to the known estrogen receptorsthat exist within cells or to estrogen receptors that bind toextracellular membranes and cause biologic effects that mimic those ofestradiol or other estrogenic compounds.

As used herein, the terms “progestational steroid” and “progestin” areused interchangeably to refer to an agent, natural or synthetic, thateffects some or all of the biological changes produced by progesterone,which is a hormone of the corpus luteum. For example, a progestin caninduce secretory changes in the endometrium. Examples of progestinsinclude, without limitation, progesterone, 17-hydroxy progesteronederivatives, 19-nor-testosterone derivatives, 19-nor-progesteronederivatives norethindrone, norethindrone acetate, norethynodrel,norgestrel, norgestimate, ethynodiol diacetate, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone levo-norgestrel, dl-norgestrel,cyproterone acetate, gestodene, desogestrol, dydrogesterone, ethynodioldiacetate, medroxyprogesterone acetate, megestrol acetate,phytoprogestins, animal-derived progestins, and metabolic derivatives ofanimal-derived progestins. These compounds also include any steroidal ornon-steroidal compounds that bind to the cytoplasmic or membrance boundprogesterone and mimic any of the biologic effects of progesterone orprogestins.

As used herein, the terms “androgenic steroid” and “androgen” are usedinterchangeably to refer to a natural or synthetic agent that stimulatesactivity of the accessory male sex organs and/or muscle developmentand/or encourages development of male sex characteristics. Examples ofsuitable androgens include, without limitation, testosterone,methyltestosterone, fluoxymesterone, testosterone cypionate,testosterone enanthate, testosterone propionate, oxymetholone,ethylestrenol, oxandrolone, nandrolone phenpropionate, nandrolonedecanoate, testosterone buccilate, stanozolol, dromostanolonepropionate, androstenedione, dehydropepiandrosterone,dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone,phytoandrogens, animal-derived androgens, and metabolic derivatives ofanimal-derived androgens. This also included any steroidal ornon-steroidal compounds that bind to either the cytoplasmic or membranebound androgen receptor and produce biologic effects that mimictestosterone or other androgenic compounds.

A “selective estrogen receptor modulator” (“SERM”) is a compound that isan estrogen analog and which exerts tissue-selective effects. Suchcompounds can function as estrogen antagonists or partial agonists.Examples of suitable SERMs include tamoxifen, raloxifene, clomiphene,droloxifene, idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384,diethylstilbesterol, genistein, nafoxidine, moxestrol,19-nor-progesterone derivatives, and 19-nor-testosterone derivatives.

A “selective androgen receptor modulator” (“SARM”) is a compound that isan androgen analog and which exerts tissue-selective effects. Suchcompounds can function as androgen antagonists or partial agonists.Examples of suitable SARMs include cyproterone acetate,hydroxyflutamide, bicalutamide, spironolactone,4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone derivatives,1,2-dihydropyridono[5,6-g]quinoline derivatives, andpiperidino[3,2-g]quinolinone derivatives.

A “selective progestin receptor modulator” (“SPRM”) is a compound thatis an progesterone analog and which exerts tissue-selective effects.Such compounds can function as progesterone antagonists or partialagonists. Examples of suitable SPRMs include RU486, CDB2914,19-nor-progesterone derivatives, 19-nor-testosterone derivatives,6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivatives,5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline derivatives, 5-alkyl1,2-dihydrochomeno[3,4-f]quinoline derivatives, and6-thiophenehydroquinoline derivatives.

Unless indicated otherwise, the hormonal steroids used in the methods ofthe present invention (e.g., estrogenic steroids, progestationalsteroids, and androgenic steroids) include the respective sex steroids(both natural and synthetic, including derivatives and analoguesthereof), as well as their respective hormone receptor modulatorcompounds (e.g., SERMs, SPRMs, and SARMs). Hormonal steroids are wellknown in the art and are described, for example, in Remington'sPharmaceutical Sciences (16th edition, 1980) at pages 925-939.

A “postmenopausal” woman is one who in the absence of hormonereplacement therapy or other medication would experience at least 12months of amenorrhea or levels of serum follicle-stimulating hormonegreater than 30 mlU/ml.

A “perimenopausal” woman is one who in the absence of hormonereplacement therapy or other medication would experience a change in herintermenstrual cycle interval and have associated symptoms of estrogendeficiency, such as vasomotor flushes, vaginal dryness, and worseningpremenstrual syndrome. Also included are women who in the absence ofhormone replacement therapy or other medication would experience lessthan 12 months of amenorrhea.

As used herein, the term “drug” means any physiologically orpharmacologically active substance that produces a local and/or systemiceffect in a mammal, such as a human.

As used herein, “pharmacologically effective amount,” “therapeuticallyeffective amount” or simply “effective amount” refers to that amount ofa drug effective to produce the intended pharmacological, therapeutic orpreventive result. For example, if a given clinical treatment isconsidered effective when there is at least a 25% reduction in ameasurable parameter associated with a disease or disorder, atherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 25%reduction in that parameter.

II. DRUG DELIVERY DEVICE

By way of example, FIG. 1 shows one embodiment of the present invention.The drug delivery device shown in this figure is offered forillustration only, and is not to be construed as limiting the invention.As one of skill in the art will appreciate, the drug delivery device canbe manufactured in a variety of shapes, sizes, and dimensions, dependingupon the particular mammal to be treated, as well as the nature andseverity of the condition to be treated. In FIG. 1, drug delivery device10 comprises a body 11 sized, shaped and adapted for placement in thevaginal tract of a human. The drug delivery device 10 comprises a body11 formed of a polymer that releases a drug(s) by diffusion into thevaginal tract of the patient. The drug delivery device 10 shown in FIG.1 comprises two unitary cylindrical segments 12 and 13, which areconnected to each other by a coupling means 14. Although FIG. 1 depictsunitary cylindrical segments one of skill in the art will appreciate thesegments can be manufactured in a variety of shapes, sizes, anddimensions. The two segments can also be directly fused without the needfor a coupling means. Such a formulation is contemplated by the multipleport mold of Example 9. Although the illustrated device comprises twosegments, the drug delivery device of the present invention can comprisethree, four, five, six, or more segments. The number and size of thesegments used for a particular application will depend, inter alia, onthe number of drugs to be delivered the dosages of the drugs, and theneed for a placebo segment(s) to prevent diffusion and interaction ofthe drugs within the device.

The drug delivery device of the present invention is formed of adrug-permeable polymeric material. Suitable polymers include, forexample, olefin and vinyl-type polymers, carbohydrate-type polymers,condensation-type polymers, rubber-type polymers, and organosiliconpolymers. In a presently preferred embodiment, the polymer is anon-absorbable thermoplastic polymer. Polymers that can be used formanufacturing the drug delivery device include, without limitation,poly(ethylene-vinyl acetate), poly(methylacrylate),poly(butylmethacrylate), plasticized poly(vinylchloride), plasticizednylon, plasticized soft nylon, plasticized poly(ethylene terephthalate),poly(ethylene), poly(acrylonitrile), poly(trifluorochloroethylene),poly(4,4′-isopropylene-diphenylene carbonate), poly(ethylenevinylesters), poly(vinyl chloridediethyl fumarate), poly(esters of acrylicand methacrylic), cellulose acetate, cellulose acylates, partiallyhydrolyzed poly(vinyl acetate), poly(vinyl butyral), poly(amides),poly(vinyl carbonate), poly(urethane), poly(olefins), and the like.These polymers and their physical properties are known to the art andcan be synthesized according to the procedures disclosed, for example,in Encyclopedia of Polymer Science and Technology (IntersciencePublishers, Inc., New York, 1971) Vol. 15, pp. 508-530; Polymers (1976),Vol. 17, 938-956; Technical Bulletin SCR-159, 1965, Shell Corp., NewYork; and references cited therein; and in Handbook of Common Polymers,Scott and Roff (CRC Press, Cleveland, Ohio, 1971).

In a preferred embodiment, the thermoplastic polymer is anethylene-vinyl acetate (EVA) copolymer. EVA copolymers, which are wellknown and commercially available materials, are particularly useful forthe controlled release of drugs by diffusion. Very suitable EVA polymersinclude, for example, the EVA material manufactured by Aldrich ChemicalCo. (Cat. No. 34,050-2); Evatane® with the designations 28-150, 28-399,and 28-400, supplied by ICI and 28.420, and in particular 28.25 and33.25 supplied by Atochem; and Elvax® with the designations 310, 250,230, 220, and 210, supplied by Du Pont de Nemours.

The release of the drug by a drug delivery device comprising EVA isdetermined to a large extent by the vinyl acetate content of thematerial. In its broadest aspects, the present invention contemplatesuse of EVA copolymers having a vinyl acetate content of about 4 to 80%by weight of the total, and a melt index of about 0.1 to 1000 grams perten minutes. Melt index is the number of grams of polymer which can beforced through a standard cylindrical orifice under a standard pressureat a standard temperature, and thus is inversely related to themolecular weight of the polymer. Preferably, the EVA has a vinyl acetatecontent of about 4 to 50% by weight and a melt index of about 0.5 to 250grams per ten minutes. In general, the rate of passage of a drug throughthe polymer is dependent on the molecular weight and solubility of thedrug therein, as well as on the vinyl acetate content of the polymer.This means that selection of particular EVA compositions will depend onthe particular drug to be delivered. By varying the composition andproperties of the EVA, the dosage rate per area of the device can becontrolled. Thus, devices of the same surface area can provide differentdosage of a drug by varying the characteristics of the EVA copolymer.The release of the drug by a drug delivery device comprising EVA is alsocontrolled by the surface area of the segment. For example, in order toincrease the rate of release of the drug one could increase the lengthand/or circumference of the segment.

In addition to varying the percentage of vinyl acetate in the copolymerand the melt index or molecular weight, the properties of the copolymercan be changed by selectively hydrolyzing its acetate groups to alcoholgroups. By converting a portion of the vinyl acetate units of thepolymer to vinyl alcohol units, the polymer is rendered more hydrophilicand the rate of passage of relatively hydrophilic drugs is increased.The percentage of vinyl acetate units hydrolyzed to vinyl alcohol unitscan vary widely but typically from about 20 to 60% are converted. Thispartial hydrolysis is a well known procedure and can be accomplishedunder standard conditions well known in the art. Exemplary hydrolysisprocedures are described in U.S. Pat. Nos. 3,386,978 and 3,494,908, bothof which are incorporated by reference herein.

The rate of diffusion of a drug from the drug delivery device is broadlydetermined by measuring the rate of the drug transferred from onechamber through a sintered glass filter of known pore size and thicknessinto another chamber and calculating from the obtained data the drugtransfer rate. The procedure is well known in the art, and described,for example, in Proc. Roy. Sci. London, Ser. A, 148:1935; J. Pharm. Sci.(1966) 55:1224-1229; and references cited therein. The diffusioncoefficient of a drug can also be experimentally determined by using thesame or similar apparatus. Methods for determining the diffusioncoefficient are described in Diffusion in Solids, Liquids and Gases, byW. Jost (Rev. Ed., Academic Press Inc. NY; 1960), Chapter XI, pp.436-488. Preferably, the drug(s) to be delivered has a molecular weightof between 50 and 2000, more preferably between 200 and 1300.

The solubility of a drug in an EVA copolymer is determined by preparinga saturated solution of the drug and ascertaining, by analysis, theamount present in a defined area of the copolymer material. For example,the solubility of the drug in the EVA copolymer is determined by firstequilibrating the polymer material with a saturated solution of the drugat a known temperature, for example 37° C., or with a pure liquid drug,if the drug is a liquid at 37° C. Next, the drug is desorbed from thesaturated polymer material with a suitable solvent for the drug. Theresultant solution is then analyzed by standard techniques such asultraviolet, visible spectrophotometry, refractive index, polarography,electrical conductivity and the like, to calculate the concentration orsolubility of the drug in the material.

The solubility of a drug in a polymeric material can be determined byvarious art known techniques. Typical methods used for the measurementof solubility are chemical analysis, measurement of density, refractiveindex, electrical conductivity, and the like. Details of various methodsfor determining solubilities are described in U.S. Public Health ServiceBulletin No. 67 of the Hygienic Laboratory; Encyclopedia of Science andTechnology (McGraw-Hill, Inc.; 1971) 12:542-556; and EncyclopaedicDictionary of Physics (Pergamon Press, Inc; 1962) 6:545-557. Also,according to Fick's Law, the rate of drug solution is directlyproportional to the area (A) of the drug, A in cm², as exposed topolymeric material and inversely proportional to the length of the paththrough which the dissolved drug must diffuse (see RemingtonPharmaceutical Science (Mack Publishing Company, 14th Ed., 1970), pp.246-269.

In a preferred embodiment, the drug delivery device of the inventionprovides “zero order kinetic” drug administration, in which a drug isreleased in a steady state, thus providing a corresponding predictableabsorption and metabolism of the drug in the body tissues. In thismanner, the delivery of drugs may be “targeted” to the specific bodyorgan, where the intended therapeutic effect is desired; other organssuch as liver, in which unintended effects may occur, may be bypassed.Thus, the efficient metabolic and therapeutic use of a drug or drugcombination may be enhanced, and the development of adverse metabolicside effects may be reduced. “Zero order kinetic” drug administration iswell known in the art. Other methods for the controlled timed release ofpredetermined amounts of pharmacologically active compositions at atarget site are also known. Methods for achieving targeted delivery ofdrugs include, for example, the use of micellar structures, such asliposomes, capsids, capsoids, polymeric nanocapsules, and polymericmicrocapsules. Liposomal suspensions (including liposomes targeted tocells with monoclonal antibodies to specific viral antigens) areparticularly useful for practicing the methods of the present invention.Liposomal formulations can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811; PCT publication WO 91/06309; and European patent publicationEP-A-43075, which are incorporated by reference herein. The use ofhighly hydrophobic formulations, such as liposomes, also increases theabsorption rate of the drug through the vaginal epithelium.

In another embodiment, the polymeric matrix is capable of being degradedby ultrasonic energy such that the incorporated drug is released at arate within a desired release range, or, in the case of nondegradablepolymers, release is enhanced presumably due to the effects ofcavitation or other mechanical effects. Representative suitable polymersfor this embodiment include polyanhydrides having the formula describedin U.S. Pat. No. 4,657,543 (Langer et al.), which is incorporated byreference in its entirety herein. The monomers in the copolymer can bedistributed regularly or at random. Since the anhydride linkage ishighly reactive toward hydrolysis, it is preferable that the polymerbackbone be hydrophobic in order to attain the heterogeneous erosion ofthe encapsulated composition. Hydrophobicity can be regulated easily,for example, by regulating the concentration of aromatic moities in thelinking backbone, or by monitoring the monomer ratio in the copolymer. Aparticularly suitable backbone comprises the acid such as 1-phenylamine,tryptophan, tyrosine or glycine. Other suitable polymers includeethylene-vinyl acetate, polylactic acid, polyglutamic acid,polycaprolactone, lactic/glycolic acid copolymers, polyorthoesters,polyamides or the like. Non-degradable polymers include ethylene-vinylacetate, silicone, hydrogels such as polyhydroxyethylmethacrylate,polyvinyl alcohol, and the like.

In addition to providing excellent release properties, the preferredcompatible, non-absorbable, non-toxic polymeric materials used in themanufacture of the inventive drug delivery device (e.g., EVA copolymer,organopolysiloxane, or other rubbery-type resilient material) do notinduce a significant tissue reaction at the site of placement in thevaginal tract of the female mammal. As a result, the drug deliverydevice of the present invention is useful in a wide variety ofapplications, such as those described in sections III-VI.

The dosage unit amount for conventional beneficial drugs as describedherein is well known in the art (see, e.g., Remington's PharmaceuticalScience (Fourteenth ed., Part IV, Mack Publishing Co., Easton, Pa.,1970)). The amount of drug incorporated in the drug delivery devicevaries depending on the particular drug, the desired therapeutic effect,and the time span for which the device provides therapy. Since theinventive device is intended to provide dosage regimes for therapy for avariety of applications and indications, there is no critical upperlimit on the amount of drug incorporated in the device. Similarly, thelower limit will depend on the activity of the drug and the time span ofits release from the device. Thus, it is not practical to define a rangefor the therapeutically effective amount of drug to be incorporated inor released by the device.

The relative amount(s) of the drug(s) to be released can be modifiedover a wide range depending upon the drug to be administered or thedesired effect. Generally, the drug can be present in an amount whichwill be released over controlled periods of time, according topredetermined desired rates, which rates are dependent upon the initialconcentration of the active substance in the polymeric matrix. In thesecond embodiment described above, the rate will also depend upon thelevel of ultrasonic energy to which it is subjected. This necessarilyimplies a quantity of active substance greater than the standard singledosage. Proportions suitable for the purposes of this invention canrange from about 0.01 to 50 parts by weight of the active substance tobetween about 99.99 and about 50 parts by weight of the polymericmatrix, preferably between about 10 and about 30 parts by weight in thecase of a drug to be implanted to give 100 parts per weight of the finalsystem. The polymeric matrix in the composition to be released can beadmixed in any convenient manner, for example by mixing the componentsas powders and subsequently forming the mixture into a desired shapesuch as by thermal forming at a temperature less than that which thecomposition will become degraded and at which the polymer has desiredmorphological properties. Such procedures are described in detail in theexamples provided herein.

The polymeric mixture utilized in the drug delivery device used in themethods of the present invention can be manufactured by standardtechniques provided that such manufacture includes process steps such asblending, mixing or the equivalent thereof for structurally defining thesystem comprising the drug(s) to be released and the polymeric matrix.For example, one suitable method for making the inventive devicescomprises mixing the polymer and an appropriate solvent, thereby to forma casting solution, mixing a known amount of the drug to be released inthe casting solution, charging the solution into a mold and then dryingthe mold, optionally under vacuum, causing the polymer to precipitate informing the matrix with the drug to be released therein. Alternatively,the polymer in the form of a powder can be admixed with the drug to bereleased in the form of a powder and then molded under adequatetemperature and pressure to the desired shape, through injection,compression, or extrusion. When two or more drugs are to be delivered,the foregoing steps of manufacture are repeated for each individualdrug, thus forming a separate molded polymeric mixture for each drug.The individual molded polymeric mixtures, each preferably containing adifferent drug, are then cut into pieces of the required length usingconventional cutting techniques, thus producing a plurality of uniformsegments. The drug delivery device or system for simultaneous deliveryof multiple drugs is then assembled by joining together, directly orindirectly, at least one segment of the molded polymeric mixture foreach drug to be delivered. Preferably, the uniform segments areassembled to form a ring shape, which has a thickness between about 1 mmand about 5 mm. The drug delivery devices of this invention can bemanufactured in a wide range of shapes, sizes and forms for deliveringthe drug(s) to different environments of use.

Alternatively, when two or more drugs are to be delivered, eachdrug:polymer mix can be molded together under adequate temperature andpressure to the desired shape, through injection, compression, orextrusion such that the two drug mixtures form one solid unit and do notrequire a coupling means. In one embodiment, the drug mixtures areinjected, preferably sequentially, into a mold comprising a single port.In an alternative embodiment, as exemplified in Example 8, herein below,the drug mixtures are injected simultaneously or sequentially into amold having multiple ports. Multiple port moldings are well known andcommercially available in the art. Such molding may be modified orcustomized for a particular application as will be appreciated by thoseof skill in the art.

In one embodiment, discussed briefly above, the ends of the segments arejoined together to form a drug delivery device using a coupling means.The coupling means can be any method, mechanism, device or materialknown in the art for bonding materials or structures together. Exemplarycoupling means include solvent bonding, adhesive joining, heat fusing,heat bonding, pressure, and the like. When a solvent is used, the endsof the segments are moistened with an organic solvent that causes thesurfaces to feel tacky, and when placed in contact the surfaces thenbond and adhere in a fluid tight union. The ends of the segments can beadhesively united to form a ring-shaped delivery device by applying anadhesive to at least one end of a segment, and then contacting theadhesive coated end or ends. For the above procedures, the solventsinclude organic solvents such as methylene chloride, ethylenedichloride, trichlorobenzene, dioxan, isophorone, tetrahydrofuran,aromatic and chlorinated hydrocarbons, mixed solvents such as 50/50ethylene dichloride/diacetone alcohol; 40/60 alcohol/toluene; 30/70alcohol/carbon tetrachloride, and the like. Suitable adhesives includenatural adhesives and synthetic adhesives, such as animal,nitrocellulosic, polyamide, phenolic, amino, epoxy, isocyanate, acrylic,silicate, organic adhesives of polymers, and the like. Adhesives arewell known to the art (see, e.g., The Encyclopedia of Chemistry (Seconded.; G. L. Clark and G. G. Hawley, editors; VanNostrand Reinhold Co.,Cincinnati, Ohio; 1966)), as well as solvents (see, e.g., Encyclopediaof Chemical Technology (Kirk-Othmer, Sec. Ed., Vol. 16, Interscience,Publishers Inc., New York, 1969)).

The lengths of the segments of the drug delivery device or system arechosen to give the required performance. Ratios of the lengths of thesegments will depend upon the particular therapeutic application,including the desired ratio and dosages of each drug to be delivered.Ratios of the lengths of the segments are contemplated to be between30:1 and 1:30, preferably between 15:1 and 1:1. When placebo segmentsare required to prevent drug diffusion and interactions, the lengths ofthe placebo segments are long enough to prevent excessive mixing of thedrugs. The length of the placebo segment depends on the nature of thepolymeric substance and its capacity to prevent permeation of the drugs.Preferably, the placebo segment completely prevents mixing of the drugs,since mixing may disturb the release pattern. However, depending uponthe drugs, some minor mixing is generally permitted, provided it doesaffect the release of the drugs in such a manner that plasma levels ofthe drugs get outside the required values. Placebo segments may also beused to close or complete the ring-shaped structure.

In an alternate embodiment, the drug delivery device is manufactured bypreparing unitary rods, rather then segments, then joining the ends ofthe rods to form a ring-shaped drug delivery device for the simultaneousrelease of multiple drugs. In this embodiment, the unitary rods areprepared essentially as described above for the segments, except thatthe polymeric mixture is molded into the shape of a rod rather than aring. In the case of vaginal rings, the polymeric substance must besufficiently pliable when dry to allow the rods to be bent and formedinto the final ring-shaped device. Thus, the step of cutting the ringinto segments may be avoided, provided that the molded rods meet thespecifications (e.g., length, diameter, etc.) to deliver the requireddosages of drugs. Alternatively, the polymeric mixture may be moldedinto over-sized cylindrical rods, which are then cut into shorter rodshaving the required dimensions. Rods of the proper size are then joinedend-to-end, as described above for the segments, to form a ring-shapeddrug delivery device.

As previously mentioned, the drug delivery device can be manufactured inany size as required. For human use, however, the outer ring diameterwill generally be between 40 mm and 80 mm, preferably between 45 mm and70 mm, and more preferably between 50 and 60 mm. Similarly, the crosssectional diameter will typically be between 0.5 mm and 12 mm,preferably between 0.5 mm and 10 mm, more preferably between 1 mm and 8mm, even more preferably between 1 and 6 mm, and most preferably between1 and 5 mm.

III. ADMINISTRATION

In another aspect, the invention relates to a method for delivering adrug to a female mammal. The method involves preparing a drug deliverydevice, as described above. The device is then positioned in the vaginaltract of the female mammal to be treated, where it is maintained for aperiod of time sufficient to deliver an effective amount of the drug tothe female mammal. Although the present invention is described in termsof an intravaginal drug delivery device, the invention contemplatesmaking and using a device for administering a drug to a male mammal. Inthis case, the device is manufactured in a shape and size appropriatefor use in a male mammal, for example as a subdermal implant or rectalsuppository. The male drug delivery device may comprise any suitableactive substance for use in a wide variety of applications and fortreating a variety of diseases and medical conditions, such as thosedescribed below, and particularly male-specific diseases such asprostate cancer.

Because of its convenience, safety, and excellent release properties,the drug delivery device of the present invention is useful in a widevariety of applications, and can be used to treat numerous conditionsand disorders. Examples of applications and therapeutic uses for thedevice include, without limitation, contraception, hormone replacementtherapy, polycystic ovarian disease, addiction, imaging, AIDS/HIV,immunology, alcohol-related disorders, infectious diseases, allergy,leukemia/lymphoma, Alzheimer's disease, lung cancer, anesthesiology,metabolic disorders, anti-infectives, neonatology, anti-inflammatoryagents, neurological disorders, arthritis, neuromuscular disorders,asthma, nuclear medicine, atherosclerosis, obesity, eating disorders,bone diseases, orthopedic, breast cancer, colon cancer, prostate cancer,cancer, parasitic diseases, cardiovascular diseases, hypertension,toxemia of pregnancy, seizures perinatal disorders, child health,pregnancy, preventative medicine, congenital defects, decision analysis,psychiatric disorders, degenerative neurologic disorders, pulmonarydisorders, dementia, radiology, dermatology, renal disorders, diabetesmellitus, reproduction, diagnostics, Rheumatic diseases, stroke, drugdiscovery/screen, surgical, endocrine disorders, transplantation, ENT,vaccines, epidemiology, vascular medicine, eye diseases, wound healing,fetal and maternal medicine, women's health, gastrointestinal disorders,gene therapy, genetic diagnostics, genetics, genitourinary disorders,geriatric medicine, growth and development, hearing, hematologicdisorders, hepatobiliary disorders, and hypertension.

Any pharmaceutically active agent used to treat the body, and which iscapable of diffusing through the polymer and being absorbed by thelining of the vaginal tract, is useful in the present invention.Preferably, though not necessarily, the drug is one that has alreadybeen deemed safe and effective for use by the appropriate governmentalagency or body. For example, drugs for human use listed by the FDA under21 C.F.R. 330.5, 331 through 361; 440-460; drugs for veterinary uselisted by the FDA under 21 C.F.R. 500-582, incorporated herein byreference, are all considered acceptable for use in the present novelpolymer networks. Examples of suitable active substances (drugs)include, without limitation, interferon, anti-angiogenesis factors,antibodies, antigens, polysaccharides, growth factors, hormonesincluding insulin, glucogen, parathyroid and pituitary hormones,calcitonin, vasopressin, renin, prolactin, thyroid stimulating hormone,corticotrophin, follicle stimulating hormone, luteinizing hormone andchorionic gonadotropins; enzymes including soybean, tyrpsin inhibitor,lysozyme, catalase, tumor angiogenesis factor, cartilage factor,transferases, hydrolases, lysases, isomerases, proteases, ligases andoxidoreductases such as esterases, phosphatases, glysidases, andpeptidases; enzyme inhibitors such as leupeptin, antipain, chrymostatinand pepstatin; and drugs such as steroids, anti-cancer drugs orantibiotics. Suitable pharmaceuticals for parenteral administration arewell known as is exemplified by the llandbook on Injectable Drugs, 6thedition, by Lawrence A. Trissel, American Society of HospitalPharmacists, Bethesda, Md., 1990 (hereby incorporated by reference).

Additional examples of drugs which may be delivered by drug deliverydevices according to this invention include, without limitation,prochlorperzine edisylate, ferrous sulfate, aminocaproic acid,mecamylamine hydrochloride, procainamide hydrochloride, amphetaminesulfate, methamphetamine hydrochloride, benzamphetamine hydrochloride,isoproterenol sulfate, phenmetrazine hydrochloride, bethanecholchloride, methacholine chloride, pilocarpine hydrochloride, atropinesulfate, scopolamine bromide, isopropamide iodide, tridihexethylchloride, phenformin hydrochloride, methylphenidate hydrochloride,theophylline cholinate, cephalexin hydrochloride, diphenidol, meclizinehydrochloride, prochlorperazine maleate, phenoxybenzamine,thiethylperzine maleate, anisindone, diphenadione erythrityltetranitrate, digoxin, isofluorophate, acetazolamide, methazolamide,bendroflumethiazide, chloropromaide, tolazamide, chlormadinone acetate,phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetylsulfisoxazole, erythromycin, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, dexamethasone and its derivatives such asbetamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,17.varies.-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,norethindrone, norethisterone, norethiederone, progesterone,norgesterone, norethynodrel, aspirin, indomethacin, naproxen,fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate,propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine,imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mandol, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine.

The compositions of the invention include a safe and effective amount ofa pharmaceutically active agent. “Safe and effective” as it is usedherein, means an amount high enough to significantly positively modifythe condition to be treated or the pharmaceutic effect to be obtained,but low enough to avoid serious side effects. As is mentioned hereinabove, compositions of the invention are considered to include bothpharmaceutical agents which treat the source or symptom of a disease orphysical disorder and personal care or cosmetic agents which promotebodily attractiveness or mask the physical manifestations of a disorderor disease.

Any conventional pharmaceutical permeation enhancer that does notinterfere with performance of the pharmaceutically active agent can beused in the preparations according to the present invention. A“permeation enhancer” is any compound that increases the uptake of thepharmaceutically active agent. Examples of permeation enhancers whichmay be used with the drug delivery devices according to this inventioninclude, without limitation, alcohols, short- and long-chain alcohols,polyalcohols, amines and amides, urea, amino acids and their esters,amides, azone or pyrrolidone and its derivatives, terpenes, fatty acidsand their esters, macrocyclic compounds, sulfoxides, tensides,benzyldimethylammonium chloride, cetyl trimethyl ammonium bromide,cineole, cocamidopropyl betaine, cocamidopropyl hydroxysultaine, dodecylpyridinium chloride, dodecylamine, hexadecyl trimethylammoniopropanesulfonate, isopropyl myristate, limonene, linoleic acid (OA), linolenicacid (LA), menthol, methyl laurate, methylpyrolidone,N-decyl-2-pyrrolidone, NLS, nicotine sulfate, nonyl-1,3-dioxolane, octyltrimethylammonium bromide, oleyl betaine, PP, polyethyleneglycol dodecylether, polyoxyethelene sorbitan monolaurate (TWEEN20), SLA, sodiumoleate, sodium lauryl sulfate, sodium octyl sulfate (SOS), sorbitanmonolaurate (S20), TWEEN20, tetracaine, and Triton X-100. Additionalexamples of permeation enhancers can be found in Sayani and Chien, Crit.Rev. Ther. Drug Carrier Syst. 13:85-184 (1996); Karande et al. NatureBiotechnology, 22, (2), 192-197, (2004); Pfister et al., Med DeviceTechnol. November-December 1990; 1(6):28-33; Mitragotri, Pharm Res.November 2000; 17(11):1354-9; and Hadgraf Int J. Pharm. Jul. 5, 1999;184(1):1-6, and references cited therein.

The drug delivery devices of the present invention are constructed insuch a way that they are retained in the vagina for periods of a day upto several months and can be readily inserted and removed, for example,in the case of the human female patient. The device, due to its uniqueshape and size, does not obstruct the cervix, as do diaphragms. In anoptional embodiment, a locally effective antimicrobial agent, forexample an antibiotic such as neomycin, nystatin and polymyxin can beincluded within the polymeric material. The improved device of thisinvention possesses numerous advantages over, for example, theintravaginal devices comprising multiple reservoirs or layers. Suchadvantages include controlled, simultaneous release of multiple drugs,release of drugs in a substantially constant ratio over a prolongedperiod of time, and ease and low cost of manufacture. The drug orcombination of drugs can be incorporated into the device in sufficientamounts to bring about the desired local and/or systemic effect. Thedrug delivery device of the present invention provides more immediateeffects, as compared to existing devices, as well as more uniform andconstant serum levels of drug during the predetermined period of timefor which the beneficial physiologic effects are desired. This is inmarked contrast to fluctuations that occur with known intravaginaldevices, for example the delayed release associated with most layereddevices, the inconsistent and unreliable release frequently observedwith multi-compartment or multi-reservoir devices, and the variations inthe pre-set fixed release ratio commonly associated with drug deliverydevices for administering multiple drugs.

IV. METHODS FOR TREATING BENIGN OVARIAN SECRETORY DISORDERS

In one embodiment, the invention relates to a method for treating benignovarian secretory disorders in female mammals (patients) using a drugdelivery device to deliver an effective amount of an LHRH composition(i.e., luteinizing hormone releasing hormone (LHRH), LHRH analogues,LHRH agonists and/or LHRH antagonists, and/or their non-peptideanalogues capable of binding to the LHRH receptor), an effective amountof an estrogenic steroid and/or its receptor modulators, and aneffective amount of a progestational steroid and/or its receptormodulators. Preferably, the device is administered to the patient duringan induced follicular phase of the menstrual cycle, beginning, ifpossible, at the onset of menses. In patients whose benign ovariansecretory disorder is characterized by amenorrhea, the methods of theinvention may be initiated at any time following the determination of anon-pregnant status. The continuous delivery of LHRH compositions incombination with sex steroid delivery for use in treating benign ovariansecretory disorders is described in detail in U.S. Pat. No. 5,130,137(Crowley, Jr.), which is incorporated by reference in its entiretyherein.

In addition, patients with disorders such that their ovaries malfunctionfor any of a variety of reasons such that their ovaries secreteexcessive sex steroids, i.e., estrogens, progestins, and/or androgens,the consequences of which are recurrent irregular menstrual periods,and/or hirsutism would be included in the methods of the invention. Themethods of the invention are especially useful in treating polycysticovarian disease, and ovarian diseases characterized by dysfunctionaluterine bleeding, amenorrhea, and especially hyper-, normo-, orhypo-gonadotropic amenorrhea, and hyperthecosis.

The methods of the invention for treating benign ovarian secretorydisorders are characterized in that they provide a continuous hormonalreplacement therapy which simulates a normal sex steroid hormone patternin the patient that is similar to those levels and/or patterns of sexsteroid secretion encountered in normal women during their ovulatorymenstrual cycles.

Progesterone and estradiol are well characterized in the art. Table 1lists current estradiol and progesterone products in human use withrelevant properties. The following publications are referenced in Table1: (1) Levy et al. Hum Reprod. March 1999; 14(3):606-10; (2) Mircuioiuet al. Eur J Drug Metab Pharmacokinet. July-September 1998; 23(3):391-6;and (3) Archer et al. Am J Obstet. Gynecol. August 1995; 173(2):471-7;discussion 477-8, all of which are herein incorporated by reference.

TABLE 1 Steady State Amount/ Serum Name Steroid Device Rate/dayConcentration Normal Menstrual Cycle Estradiol 50-700 ug 50-500 pg/mlSex Steroid Secretion Progesterone 2-6 ng/ml Vaginal Estring Estradiol 2mg 22 ug 8 pg/ml Rings Intravaginal Estrace Estradiol 0.1 mg GelsVagiFem 25 ug 25 ug Crinone Progesterone 45 & 90 mg 45/90 mg 7 ng/mlTransdermal Alora Estradiol 1.5, 2.3, 50, 75, and 60-100 pg/ml and 3.0mg 100 ug Climara 2.0, 3.8, 25, 50, 75 22-106 pg/ml 5.7 or or 100 ug 7.6mg Vivelle 0.39, 25, 37.5, 34-104 pg/ml 0.585, 0.78, 50, 75, or 1.17, or100 ug 1.56 mg Oral ORTHO- Estradiol 1 mg 1 mg/day PREFEST Estrace 0.5,1 & 0.5, 1 & 2 mg 2 mg/day PROMETRIUM Progesterone 100/200 mg 100/200 mg~3 ng/ml Vaginal Academic Progesterone 50/100 mg 50/100 mg 6-7 ng/mlTablets/ Research 100/200 mg 100/200 mg 6-10 ng/mL Suppository 100/200mg 100/200 mg 10-14 ng/mL Our Target WHI Estradiol 3 mg 100 ug 100 pg/mLProgesterone 630 mg 45 mg 6 ng/mL D-Trp6- 5 mg 4 ug/Kg/day 10-100 pg/mLPro9-Net- GnRH Name T_(max) C_(max) T_(1/2) Indication Normal MenstrualCycle Midcycle 500 pg/ml Sex Steroid Secretion Midluteal 35 ng/ml 12 h —Vaginal Estring 1 h 63 pg/ml Rx. of Rings urogenital Sx. in menopauseIntravaginal Estrace Rx of vulval and Gels vaginal atrophy VagiFem 50pg/ml Rx of atrophic vaginitis Crinone 5.6-6.8 h 14 ng/ml 34-55 hprogesterone supplementation or replacement as part of an IVFTransdermal Alora 18-24 h 92-144 pg/ml 2 h Rx of vaso- Climara 18-24 h32-174 pg/ml 4 h motor Sx. in Vivelle 1 h 46-145 pg/ml 5.9-7.7 hmenopause Rx of vulvar and vaginal atrophy Oral ORTHO- 7 h 27.4 pg/ml 16h Rx. of vasomotor PREFEST symptoms in the Estrace menopause PROMETRIUM1.5/2.3 h 17/28 ng/ml Prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women Rx'd with estrogens VaginalAcademic 6.1/6.4 h 20/31 nmol/l 13.2/13.7 h 1 Tablets/ Research 4 h10-15 ng/mL 9-14 h 2 Suppository 6.7-20.9 ng/mL 3 Our Target WHI

The methods of the invention for treating benign ovarian secretorydisorders comprise providing a drug delivery device having two or moresegments, wherein a first segment comprising a drug-permeable polymericsubstance and a LHRH, and a second segment comprising an effectiveamount of an estrogenic steroid or selective estrogen receptor modulator(SERM). The drug delivery device is then inserted into the vagina of thefemale mammal, such as a human female, to release effective amounts ofthe hormones. The drug-permeable polymeric substance may be athermoplastic polymer, such as an ethylene-vinyl acetate copolymer. Thedrug delivery device may be in the shape of a ring, a wafer, or asuppository. In a preferred embodiment, the drug delivery device is aring-shaped device such as the one described above in Section II.

Estrogenic steroids which can be used according to this aspect of theinvention include natural estrogenic hormones and congeners, including,but not limited to, estradiol, estradiol benzoate, estradiol cypionate,estradiol valerate, estrone, piperazine, estrone sulfate, ethinylestradiol, polyestradiol phosphate, estriol, and estrone potassiumsulfate. Synthetic estrogens can be used in the invention, including,but not limited to, benzestrol, chlorotrianisene, dienestrol,diethystilbestrol, diethylstilbestrol diphosphate, and mestranol. In thepreferred embodiment of this invention, natural estrogenic hormones areused. Also included are estrogens developed for veterinary use,including equine estrogens such as equilelinin, equilelinin sulfate andestetrol.

In addition to the above-described estrogenic compounds, estrogenicsteroids useful in accordance with this aspect of the invention includeselective estrogen receptor modulators (SERMs), which are estrogenanalogues having tissue-selective effects. Examples of suitable SERMsinclude tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene,toremifene, tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol,genistein, nafoxidine, moxestrol, 19-nor-progesterone derivatives, and19-nor-testosterone derivatives.

Typical dose ranges for estrogenic steroids will depend upon theestrogenic steroid compounds chosen for use in the methods of theinvention and the female mammal patient. As an example, for estradiol,for the human adult female, typical dose ranges will be administeredsuch that the serum level of estradiol will be from about 20 to about200 pg/ml. Preferably the serum level of estradiol is from about 50 toabout 150 pg/ml; more preferably from about 80 to about 120 pg/ml.Levels of the synthetic estrogens which are the physiologicalequivalents of these ranges of estradiol can be used according to themethods of the invention.

Plasma estradiol can be measured by a variety of means well known in theart, e.g. ELISA. For example plasma estradiol levels can be measured bya microparticle enzyme immunoassay (MEIA) technology utilizing the AxSYMimmunoassay system (Abbott) with the Estradiol reagent pack (Abbott,Cat.#7A63-20) according to manufacturer's protocol.

Progestational steroids which can be used according to the inventiondescribed herein include, but are not limited to, dydrogesterone,ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesteroneacetate, norethindrone, norethindrone acetate, norethynodrel,norgestrel, progesterone, and megestrol acetate.

Veterinarian progestational steroids can also be used in this invention,including acetoxyprogesterone, chlormadinone acetate, delmadinoneacetate, proligesterone, melengestrol acetate, and megestrol acetate.

Other progestational steroids useful in accordance with this aspect ofthe invention include selective progestin receptor modulators (SPRMs).Examples of suitable SPRMs include RU486, CDB2914, 19-nor-progesteronederivatives, 19-nor-testosterone derivatives,6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivatives,5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline derivatives, 5-alkyl1,2-dihydrochomeno[3,4-f]quinoline derivatives, and6-thiophenehydroquinoline derivatives.

Typical dose ranges for progestational steroids will also depend uponthe progestational steroid chosen for use in this invention and upon thefemale mammal patient. For a human adult female, typical dose rangeswill be an amount which can be administered such that the patient'sserum levels of progesterone will be from about 1 to about 20 ng/ml.Preferably the serum level of progesterone is from about 1 to about 15ng/ml; more preferably from about 2 to about 10 ng/ml.

Plasma progesterone can be measured by a variety of methods well knownin the art, e.g., ELISA. For example, Levy et al. Human Reproduction,14:606-610 (1999), which is herein incorporated by reference teachesthat plasma progesterone may be measured by the IMMULITEchemiluminescent immunoassay (Diagnostic Products Corporation, LosAngeles, Calif.).

In the combined administration of an effective dose of LHRH composition,the dose range will depend upon the particular LHRH composition used,but will be in an amount sufficient to suppress LH and FSH secretion bythe action of the LHRH composition on the pituitary membrane LHRHreceptor and/or block its subsequent biological action. As will beunderstood by one of skill in the art, the effective dose ranges will becompound specific and will depend upon patient characteristics, such asspecies, age and weight. An effective dose range of LHRH composition maybe determined by routine testing by one of skill in the art, withoutundue experimentation. Further, the LHRH composition may comprise oneLHRH composition or may comprise two or more LHRH compositions. Ingeneral, it is expedient to administer the active LHRH composition inamounts between about 0.01 to 10 mg/kg of body weight per day. It willbe understood in the art that this range will vary depending uponwhether a LHRH antagonistic analogue or a LHRH agonistic analogue, or acombination of the two, is administered.

It well known in the art how to measure FSH and LH levels in plasma. Forexample FSH and LH can both be measured by ELISA. Levy et al. teachesthat leutinizing hormone and FSH can be measured by Enzyme test kit(Boehringer Mannheim Immunodiagnostics, Sussex, UK).

As is known in the art, menstrual cycles are characteristic of humansand primates and do not occur in other vertebrate groups. Other mammalshave estrous cycles. Both menstrual cycles and estrous cycles areregulated by the same interaction of the hypothalamic, pituitary andovarian hormones, and the effects of the ovarian hormones on thereproductive tract are comparable. The menstrual cycle is generallydivided into two phases: the follicular phase and the luteal phase. Thefollicular phase extends from the onset of menstruation to ovulation(approximately 14 days in the humans). The luteal phase extends fromovulation to the beginning of menstruation (approximately another 14days in humans).

The estrous cycle is generally divided into four phases: the estrusphase, the metestrus phase, the diestrus phase, and the proestrus phase.Ovulation typically occurs during the estrus phase and thus the estrusand metestrus phases roughly correspond to the luteal phase. Thediestrus phase and proestrus phase roughly correspond to the follicularphase. As used herein, these phases are all referred to as “follicular”and “luteal phases” of the menstrual cycle, although it is to beunderstood that the invention described herein also applies to mammalswith estrous cycles. Appropriate dose ranges can be determined formammals with estrous cycles by one of skill in the art through routinetesting, without undue experimentation. In mammals with estrous cycles,it may also be desirable to control estrous behavior. The dose rangeadministered for prevention of pregnancy and reduction of estrousbehavior can also be determined by one of skill in the art by routinetesting. The methods would be especially useful in treating, forexample, female animals diagnosed with cystic ovarian disease (COD) andespecially when such cysts manifest themselves as nymphomania,continuous estrus, irregular estrus, first estrus postpartum, anestrussince calving, anestrus after estrus, persistant corpus luteum oranestrus after insemination.

The methods of this invention may be administered to mammals includingbut not limited to humans, primates, equines, canines, felines, bovines,ovines, ursines, and fowl.

LHRH compositions are absorbed very well across a wide variety ofsurfaces. Thus oral, subcutaneous, intramuscular, intravenous, vaginal,nasal, transdermal and aural routes of administration have all proven tobe effective. In a preferred embodiment of this invention,administration of the delivery system is made via the vaginal route.Approximately 1-10% or greater of the LHRH composition is absorbedthrough the vaginal epithelium. Thus, the LHRH composition isadministered via a vaginal delivery system using a matrix which permitstransvaginal absorption. In this same first vaginal delivery system, aneffective dosage of physiological amounts of an estrogenic steroid isalso delivered. This delivery system allows complete suppression ofgonadotropins, removal of reproductive function of the ovaries, totalsuppression of ovarian steroidogenesis, and yet still effects aphysiological replacement of sufficient levels of estrogen to thwart thelong term side effects of the estrogen deficiency that occurs duringLHRH administration. This vaginal delivery device is preferablyadministered during the follicular phase of the menstrual cycle,beginning at the onset of menses.

The methods of the invention would also be useful to induce breeding. Inseasonal breeding animals, such as sheep, sequential application of aninduced follicular phase of variable length followed by an inducedluteal phase would induce subsequent estrous. Such induced estrousprovides a more timely and experimentally controllable breeding. Themethods of the invention would also serve to induce breeding at a higherfrequency, for example, to induce breeding more than once or twice ayear.

V. METHODS FOR PREVENTING PREGNANCY IN MAMMALS

In another embodiment, the invention relates to a method for preventingpregnancy in a mammal. The method comprises administering an effectiveamount of an LHRH composition (i.e., luteinizing hormone releasinghormone (LHRH), LHRH analogues, LHRH agonists and/or LHRH antagonists,and/or their non-peptide analogues capable of binding to the LHRHreceptor) and an effective amount of an estrogenic steroid and/or aselective estrogen receptor modulator (SERM) during the follicular phaseof the menstrual cycle, beginning at the onset of normal menses. Next,during the luteal phase of the menstrual cycle, the method comprisesadministering an effective amount of a LHRH composition, an effectiveamount of an estrogenic steroid and/or SERM, and an effective amount ofa progestational steroid and/or a selective progestin receptor modulator(SPRM). Following the luteal phase, the LHRH composition and aneffective amount of an estrogenic steroid and/or SERM are administered,at which time menstruation would typically occur. The continuousdelivery of LHRH compositions in combination with sex steroid deliveryfor use as a contraceptive is described in detail in U.S. Pat. No.4,762,717 (Crowley, Jr.), which is incorporated by reference in itsentirety herein.

The LHRH composition (i.e., luteinizing hormone releasing hormone(LHRH), LHRH analogues, LHRH agonists and/or LHRH antagonists, and/ortheir peptide or non-peptide analogues capable of binding to the LHRHreceptor), estrogenic steroid and/or SERM, and progestational steroid ornon-steroidal analogues and/or SPRM, which are useful in accordance withthis aspect of the invention, are described above.

Typical dose ranges for estrogenic steroids and SERMs will depend uponthe estrogenic steroid compound chosen for use in this invention and thefemale mammal patient. For a human adult female, typical dose rangeswill be administered such that the serum level of estradiol will be fromabout 50 to about 140 pg/ml. Preferably the serum level of estradiol isfrom about 20 to about 150 pg/ml; more preferably from about 80 to about120 pg/ml. Serum estrogenic steroid levels can be measured as describedin Section IV.

Typical dose ranges for progestational steroids and SPRMs will alsodepend upon the progestational steroid chosen for use in this inventionand upon the female mammal patient. For a human adult female, typicaldose ranges will be an amount which can be administered such that thepatient's serum levels of progesterone will be from about 1 to about 20ng/ml. Preferably the serum level of progesterone is from about 1 toabout 15 ng/ml; more preferably from about 2 to about 10 ng/ml. Serumprogesterone levels can be measured as described in Section IV.

In the combined administration of an effective dose of LHRH composition,the dose range will depend upon the particular LHRH composition used,but will be in an amount sufficient to suppress LH and FSH secretion bythe action of the LHRH composition on the pituitary membrane receptorand block its subsequent actions. As will be understood by one of skillin the art, the effective dose ranges will be compound specific and willdepend upon patient characteristics, such as age and weight. Aneffective dose range of LHRH composition may be determined by routinetesting by one of skill in the art, without undue experimentation.Further, the LHRH composition may comprise one LHRH composition or maycomprise two or more LHRH compositions. In general, it is expedient toadminister the active LHRH composition in amounts between about 0.01 to10 mg/kg of body weight per day. It will be understood in the art thatthis range will vary depending upon whether a LHRH antagonistic analogueor a LHRH agonistic analogue, or a combination of the two, isadministered. Serum LH and FSH levels can be measured as described inSection IV.

As is known in the art, menstrual cycles are characteristic of humansand primates and do not occur in other vertebrate groups. Other mammalshave estrous cycles. Both menstrual cycles and estrous cycles areregulated by the same interaction of the hypothalmic, pituitary andovarian hormones, and the effects of the ovarian hormones on thereproductive tract are comparable. The menstrual cycle is generallydivided into two phases: the follicular phase and the luteal phase. Thefollicular phase extends from the onset of menstruation to ovulation(approximately 14 days in humans). The luteal phase extends fromovulation to the beginning of menstruation (approximately another 14days in humans).

The estrous cycle is generally divided into four phases: the estrusphase, the metestrus phase, the diestrus phase, and the proestrus phase.Ovulation typically occurs during the estrus phase and thus the estrusand metestrus phases roughly correspond to the luteal phase. Thediestrus phase and proestrus phase roughly correspond to the follicularphase. As used herein, these phases are all referred to as follicularand luteal phases of the menstrual cycle, although it is to beunderstood that the inventions described herein also apply to mammalswith estrous cycles. Appropriate dose ranges can be determined formammals with estrous cycles by one of skill in the art through routinetesting, without undue experimentation. In mammals with estrous cycles,it may also be desirable to control estrous behavior. The dose rangeadministered for prevention of pregnancy and reduction of estrousbehavior can also be determined by one of skill in the art by routinetesting.

The method of this invention may be administered to mammals includingbut not limited to humans, primates, equines, canines, felines, bovines,and ursines.

The methods of the invention for preventing pregnancy in a mammalcomprise providing a drug delivery device having two or more segments,wherein a first segments comprising a drug-permeable polymeric substanceand a LHRH, and a second segment comprising an effective amount of anestrogenic steroid or SERM. The drug delivery device is then insertedinto the vagina of the female mammal, such as a human female, to releaseeffective amounts of the hormones. The drug-permeable polymericsubstance may be a thermoplastic polymer, such as an ethylene-vinylacetate copolymer. The drug delivery device may be in the shape of aring, a wafer, or a suppository. In a preferred embodiment, the drugdelivery device is a ring-shaped device such as the one described belowin Section V.

In one embodiment of this aspect of the invention, the device describedabove is removed following maintenance of the LHRH/estrogenic steroiddelivery system during the follicular phase (typically fourteen days inhumans), and replaced by a second vaginal delivery system which has theLHRH/estrogenic steroid combination and the effective physiologicalamount of a progestational steroid or SPRM. This second delivery systemis administered during the luteal phase of the menstrual cycle(typically fourteen days in humans), until the onset of normal menses.This second delivery system provides an artificial luteal phase to thefemale.

Following the second vaginal delivery system, and readministration ofthe first vaginal delivery system, menstruation occurs, reassuring thepatient of lack of conception. Further, the administration of aprogestational steroid in the second delivery system permittingmenstruation, also avoids endometrial hyperplasia.

In an alternate embodiment of this aspect of the invention, the twoformulations described above (the LHRH/estrogenic steroid formulationand LHRH/estrogenic/progestational steroid formulation) are combined inone drug delivery device, which is designed to remain in the vagina ofthe female for the entire menstrual cycle. In this embodiment, the drugdelivery device comprises at least one cylindrical unitary segment perhormonal formulation, or, alternatively, at least one cylindricalunitary segment per active ingredient (i.e., LHRH, sex steroid, or sexsteroid modulator). The choice of polymeric material and the ratio ofpolymeric material to LHRH/sex steroid/sex steroid modulator arepreselected for each segment to provide the appropriate release kineticsfor the individual steroids and/or steroidal formulations. By selectingthe polymeric material based on its release properties and adjusting theratio of polymeric material to drug, the method of the present inventionprovides the pre-set timed delivery of LHRH, estrogenic steroid, andprogestational steroid at the appropriate phase of the menstrual cycleto achieve the desired contraceptive effect. For example, this“combined” device would release LHRH and/or its agonists or antagonistscontinuously for 30 days in combination with an estrogenic compound.After approximately two weeks of such therapy, the device would releaseprogesterone or a progestational steroid or non-steroidal compound forthe last 14 days of the cycle following which its declining levels wouldinduce a menstrual bleed due to decreasing progesterone support exactlyas occurs in the normal female menstrual cycle. In one embodiment, thetwo formulations described above (the LHRH/estrogenic steroidformulation and LHRH/estrogenic/progestational steroid formulation)would exhibit the characteristics described in Table II.

TABLE II Drug Release from Drug Loading Circulation the Ring for 21 daysDrug Level per day of Release Ring A Estradiol 100 pg/mL 100 μg 2.1 mgD-Trp6-Pro9- 10-100 pg/mL 4 μg/Kg 5 mg Net-GnRH Ring B Estradiol 100pg/mL 100 μg 2.1 mg Progesterone 6 ng/mL 45 mg 630 mg D-Trp6-Pro9-10-100 pg/mL 4 μg/Kg 5 mg Net-GnRH

VI. HORMONE REPLACEMENT THERAPY

In another aspect, the invention relates to a method for treatingperimenopausal or postmenopausal women, including women of all ageshaving premature ovarian failure (e.g., young women who have had anablation of ovarian function due to surgery, radiation, orchemotherapy). In this aspect, the invention provides methods fortreating a decrease in estrogen secretion as well as relieving thesymptoms and signs associated with menopausal, perimenopausal, andpost-menopausal periods in women. In one embodiment, the method involvesproviding a drug delivery device, as described in Section V below,comprising a drug-permeable polymeric substance and (i) an androgen or aselective androgen receptor modulator (SARM), (ii) an estrogen or aselective estrogen receptor modulator (SERM), and (iii) a progestin or aselective progestin receptor modulator (SPRM) or any combination of theabove depending upon the individual patient's needs. The drug deliverydevice is inserted into the vagina of the woman to release an effectiveamount of the sex steroids or sex steroid modulators to the woman. Thecontinuous delivery of replacement hormones for treating perimenopausalor postmenopausal women is described in detail in U.S. Ser. No.09/585,935, filed Jun. 2, 2000 (K. A. Martin et al.), which isincorporated by reference in its entirety herein.

In another embodiment, the method of the present invention involvesproviding a drug delivery device, as described below, comprising adrug-permeable polymeric substance and (i) a SERM and (ii) an androgenor a SARM. Optionally, the drug delivery device also includes (iii) aprogestin or a SPRM. The drug delivery device is inserted into thevagina of the woman, where it releases a therapeutically effectiveamount of the active agents (SERM, an androgen or SARM, and optionally aprogestin or SPRM), thereby relieving the symptoms and signs associatedwith the menopausal, perimenopausal and postmenopausal periods.

In yet another embodiment, the method of the present invention involvesthe use of a drug delivery device comprising (i) a SERM and (ii) anestrogen, and optionally (iii) a progestin or SPRM. The drug deliverydevice is inserted into the vagina of the woman, where it releases atherapeutically effective amount of the active agents (SERM, estrogen,and optionally progestin or SPRM), thereby relieving the symptoms andsigns associated with the menopausal, perimenopausal and postmenopausalperiods.

In another variation of the above, the drug delivery device contains (i)a SERM, (ii) an estrogen, and (ii) an androgen or SARM, and optionally(iv) a progestin or SPRM. The drug delivery device is inserted into thevagina of the woman, where it releases a therapeutically effectiveamount of the active agents (SERM, estrogen, androgen or SARM, andoptionally progestin or SPRM), thereby relieving the symptoms and signsassociated with the menopausal, perimenopausal and postmenopausalperiods.

Virtually all postmenopausal and perimenopausal women can be treatedwith the methods of the invention with or without the addition of LHRHor one of its peptide or non-peptide analogues. If desired, such a womancan be identified as being in need of hormone replacement therapy (usingstandard criteria, as described, for example, by the American College ofPhysicians Guidelines, which is incorporated herein by reference) priorto treatment of the woman with the methods of the invention. A varietyof therapeutic regimens are suitable for use in the invention, andpractitioners of ordinary skill in the art can readily optimize aparticular regimen for a particular woman by monitoring the woman forsigns and symptoms of hormone deficiency, and increasing or decreasingthe dosage and/or frequency of treatment as desired.

In this embodiment of the invention, the androgen is administered at adaily dosage of 0.01 μg to 5 mg/kg of body weight (e.g., 1 μg/kg to 5mg/kg), the estrogen typically is administered at a dosage of 0.01 μg/kgto 4 mg/kg (e.g., 0.2 μg/kg to 100 μg/kg), and the progestin typicallyis administered at a dosage of 0.02 mg/kg to 200 mg/kg (e.g., 2 μg/kg to10 mg/kg). A SARM typically is administered at a daily dosage of 0.01μg/kg to 100 mg/kg of body weight (e.g., 1 μg/kg to 4 mg/kg), a SERMtypically is administered at a dosage of 0.01 μg/kg to 100 μg/kg (e.g.,1 μg/kg to 2 mg/kg), and a SPRM typically is administered at a dosage of0.01 μg/kg to 100 mg/kg (e.g., 1 μg/kg to 30 mg/kg). Typically, thewoman will be treated over the course of several months or years, oreven life-long to ameliorate the signs and symptoms resulting fromnatural or induced impairment of ovarian function.

In one example of a suitable method of treating perimenopausal women,the therapeutic regimen entails administering to the woman a drugdelivery device comprising each of (i) an androgen or SARM, (ii) anestrogen or SERM, and (iii) a progestin or SPRM for 13 to 14 days,followed by administering each of (i) an estrogen or SERM and (ii) anandrogen or SARM for 13 to 14 days. The dosages listed above aresuitable. In this embodiment, the drug delivery device is removedfollowing the initial 13-14 day period (the follicular phase), andreplaced by a second drug delivery device containing the estrogen orSERM and androgen or SARM combination. Alternatively, the twoformulations (the androgen/SARM, estrogen/SERM and progestin/SPRMformulation; and the estrogen/SERM and androgen/SARM formulation) arecombined in a single drug delivery device, which is designed to remainin the vaginal tract of the female for the entire menstrual cycle, asdescribed above in Section III in the context of contraception.

In one example of a suitable method of treating menopausal women, thetherapeutic regimen entails administering to the woman a drug deliverydevice comprising each of (i) an androgen or SARM, (ii) an estrogen orSERM, and (iii) a progestin or SPRM. The dosages listed above aresuitable. In this embodiment, the drug delivery device is designed toremain in the vaginal tract of the patient for at least 30 days,preferably several months (e.g., 2-4 months).

In another method, the woman is treated with a drug delivery devicecontaining each of (i) a SERM, (ii) an androgen or SARM, and,optionally, (iii) a progestin or SPRM. In a typical therapeutic regimen,the device remains in the vaginal tract of the woman for at least 30days, delivering a daily dose of active agents at the dosages listedabove. Usually, the woman will be treated over the course of severalmonths or years, or even life-long to relieve her of the signs andsymptoms resulting from natural or induced impairment of ovarianfunction.

Alternatively, the woman can be treated with a drug delivery devicecontaining each of (i) a SERM and (ii) an estrogen, and, optionally,(iii) a progestin or SPRM. In a typical therapeutic regimen, thiscombination of steroids is administered to the woman for at least 30days at the daily dosages listed above. Usually, the woman will betreated over the course of several months or years, or even life-long torelieve her of the signs and symptoms resulting from natural or inducedimpairment of ovarian function.

In still an alternative method, the woman can be treated with a drugdelivery device containing each of (i) a SERM, (ii) an estrogen, (iii)an androgen or SARM, and, optionally, (iv) a progestin or SPRM. In atypical therapeutic regimen, this combination of steroids isadministered to the woman for at least 30 days at the daily dosageslisted above. Usually, the woman will be treated over the course ofseveral months or years, or even life-long to relieve her of the signsand symptoms resulting from natural or induced impairment of ovarianfunction.

For long-term delivery of replacement hormones, the device willtypically contain sufficient quantities of the sex steroids or sexsteroid modulators to provide a 1 to 48 month supply, a 1 to 36 monthsupply, a 1 to 24 month supply, preferably a 1 to 12 month supply, andmost preferably a 1 to 6 month supply of replacement hormones.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, drawings and the accompanying claims. For example, thefollowing examples illustrate the practice of the invention forcontrolled release of progesterone, estradiol, and LHRH or gonadotropinreleasing hormone (GnRH). As described elsewhere herein, the inventionis useful in a wide variety of applications and for treating numerousconditions and disorders. Thus, as will be appreciated by those skilledin the art, drug delivery devices according to the invention can bemanufactured to contain any number of segments or rods, comprising anysuitable drug or drug combination, and may be used to treat a variety ofindications, in both male and female mammals.

EXAMPLES Example 1 Preparation of a Vaginal Ring for Controlled Releaseof Progesterone, Estradiol and Gonadotropin Releasing Hormone (GnRH)

The intravaginal drug delivery device illustrated in FIG. 1 was preparedusing poly(ethyl-co-vinyl acetate) (EVA) manufactured by AldrichChemical Co. (Cat. No. 34,050-2; Lot No. 07322DR). 630 (milligrams) mgof progesterone (Sigma Corp.; Cat. No. P-3972) or 2.8 mg of estradiol(Sigma Corp.; Cat. no. E-1072) were each dissolved separately inapproximately 5 mL of dichloromethane (Fluka Chem. Co.; Cat. No. 66740;Lot No. 404915/162800) in separate scintillation vials. Next, polymericmixtures were prepared by adding 1400 mg of EVA to the progesteronesolution and 1800 mg of EVA to the estradiol solution, and mixing theEVA/drug compositions using a rotary shaker. The resulting mixtures werethen solvent cast in dry ice using ethanol as the solvent (Pharmco; Cat.No. 111 USP 200 CSGL; Lot No. M8241). The solvent was allowed toevaporate overnight, and the dry EVA/drug mixtures were then ground intopowders. The EVA/drug powders were placed in an injection molding unit(DSM, Geleen, Holland). The injector was heated to approximately 80° C.The molten EVA/drug compositions were extruded into stainless steel mold(the mold is at 10° C.), creating a 1800 mg ring with an outer diameterof 50 mm and a cross section of 4 mm.

Similarly, a polymeric ring comprising GnRH agonist(D-Trp6-Pro9-Net-GnRH) was prepared by dissolving 10 mg of GnRH agonistand 450 mg of methyl cellulose in approximately 5 mL methylene chloride.1800 mg EVA was added. The EVA/drug mixture was dried and the resultingpowder was placed in an injection molding unit (DSM, Geleen, Holland).The injector was heated to approximately 80° C. The moltenEVA/GnRH/cellulose compositions was extruded into stainless steel mold(the mold is at 10° C.), creating a 1800 mg EVA ring with an outerdiameter of 50 mm and a cross section of 4 mm.

The EVA rings containing estradiol, progesterone, and GnRH were eachaseptically cut into unitary cylindrical segments of the appropriatelengths, i.e., lengths that contain sufficient quantities of drug toprovide therapeutically effective amounts of each drug. The pieces ofthe EVA loaded drug were placed back in the mold and neat EVA wasinjected to the mold to connect the pieces together. If needed, a fourth(placebo) segment of EVA may be used to complete the ring structure.

The vaginal ring described herein was designed to deliver 21-day dosagesof each drug, i.e., 100 micrograms (μg) per day of estradiol, 6milligrams (mg) per day of progesterone, and 240 μg per day of GnRH.

Example 2 Intravaginal Administration of GnRH to Rhesus Monkeys

Compositions comprising GnRH were prepared using an over-the-counterhydrogel sold under the name Replens® (Columbia Laboratories, Inc.,Livingston, N.J.). Compositions comprising GnRH were prepared by mixing10 mg of GnRH with 2 g of Replens®. 2 g of the GnRH/Replens® mixture wasthen placed in the vaginal tracts of five Rhesus monkeys and allowed toremain there for 9 hours. Blood samples were obtained at one hourintervals for the full 9 hour course. The blood samples had the serumseparated from the clot by centrifugation and samples were subjected toan RIA assay to measure GnRH. GnRH levels were determined based on atraditional double antibody RIA for GnRH (this protocol can be modifiedto also measure GnRH agonists, or GnRH antagonists by varying theantibody).

Briefly, anti-GnRH was added to standard and test samples and incubatedat room temperature for 20-24 hours. The I-125 labeled GnRH were dilutedto 21,000-22,5000 CPM/100 μl solutions and added to each tube of theassay and to total count tubes and incubated at room temperature for20-24 hours. 100 μl of sheep anti-rabbit gamma globulin (SARGG) and 100μl of 16% PEG (Fisher, Cat. #P156-500) was added to each tube andincubated at 4° C. for 1 hour. Samples were washed with 2 ml ofdistilled water and centrifuged at 3000 rpm for 20 minutes. Supernatantswere decanted and pellets were counted for one minute in a gammacounter. FIG. 2 shows the serum levels of GnRH in three monkeys as afunction of time.

This example shows that GnRH (molecular weight of approximately 1,100)can traverse the vaginal epithelium in primates in sufficient quantitiesto achieve therapeutic serum levels of the hormone.

Example 3 Simultaneous Release of Estradiol, Progesterone, GNRH from anEVA Ring

Intravaginal drug delivery devices comprising estradiol, progesterone,and GnRH were prepared as described in Example 1. Estradiol,progesterone and GnRH rings were placed in 100 ml of release media(70:30 PBS:EtOH, pH=6) at 37° C. on as rotary shaker (100 RPM). At theindicated time points media was collected and measured by HPLC on anAgilent 1100 Series HPLC (Agilent, Forest City, Calif.). Estradiol andprogesterone were detected by UV at 230 nm while GnRH was measured at215 nm. Results were calculated based on the area under the curvecompared to a 5 point calibration curve. Results were expressed as thecumulative release in μg released over the course of the experiment.

FIG. 3 shows the in vitro zero order kinetic release of estradiol andprogesterone over a 21-day period. FIG. 4 shows the in vitro zero orderkinetic release of GnRH during this same period.

This example demonstrates stable zero order release kinetics forestradiol, progesterone, and GnRH over a 14 to 21 day period, withoutdrug interactions or interference. The example also shows that vaginalrings produced in accordance with the present invention have sufficientcapacity to sustain at least 21 days of adequate flux rates of GnRH(i.e., delivery rates capable of producing a serum level of 3-6 ng/ml inthe circulation) to completely silence ovarian production of sexsteroids, thereby totally suppressing ovulation. The vaginal rings alsohave sufficient capacity to deliver therapeutically effective amounts ofthe naturally secreted ovarian hormones, estradiol and progesterone, torestore both normal levels and patterns of each and to produce a normal,monthly menstrual flow. Natural estradiol should be administered at arate of 100 μg/day, whereas progesterone should be delivered atapproximately 45 mg/day, i.e., rates that have been demonstrated toproduce serum levels of approximately 100 pg/ml of estradiol and 6,000μg/ml/day of progesterone.

Example 4 Release Kinetics of Estradiol and Progesterone from an EVAMatrix

EVA mixtures containing estradiol and progesterone where prepared asdescribed in Example 1 above, except that the EVA/drug mixtures were notfurther processed by injection molding or extrusion to form rings. Afterdrying, the compositions (discs) were evaluated for their releasekinetics. Estradiol and progesterone were placed in 100 ml of releasemedia (70:30 PBS:EtOH, pH=6) at 37° C. on a rotary shaker (100 RPM). Atthe indicated time points, media was collected and measured by HPLC onan Agilent 1100 Series HPLC (Agilent, Forest City, Calif.). Estradioland progesterone were detected by UV at 230 nm. Results were calculatedbased on the area under the curve compared to a 5 point calibrationcurve. Results are shown in FIG. 5.

As shown in FIG. 5, the dry EVA/drug mixtures provide bi-phasic releasekinetics with a total recovery of 70% over a 21-day period.

Example 5 Effect of Cellulosics on Release Kinetics

EVA mixtures containing progesterone and estradiol where prepared asdescribed in Example 1 above, except that the EVA/drug mixtures were notfurther processed by injection molding or extrusion. Also, varyingamounts of a commercially available cellulosic, Methocel® (DowChemicals, Co., Midland, Mich.) were incorporated into the mixtures toevaluate the effect of cellulosics on release kinetics. Briefly,estradiol and progesterone were each dissolved in two separate vials ofethanol, and a low concentration (5% by weight) and a high concentration(25% by weight) of Methocel® was added to the estradiol and progesteronevials. The solutions were slowly emulsified into a methylene chloridesolution containing EVA. The resulting emulsions were solvent-castedinto a mold, which was then cooled on dry ice. Following sublimation,the solvents were cut into 1 cm×1 cm samples, and placed inscintillation vials, to which 0.1 M phosphate buffered saline (pH 6.10)and ethanol were added in a 70:30 ratio. The vials were placed in a 37°C. incubator on a shaker rotating at 100 RPM. The buffer solution wasreplaced at predetermined time points. The released amount of estradioland progesterone was determined by UV/VIS spectrophotometry at 280 nm or250 nm, respectively. Next, the release kinetics were determined byplotting the cumulative release amounts as a function of time. As shownin FIG. 6, the addition of Methocel® results in pseudo zero orderrelease kinetics. Also, the higher the ratio of cellulosics toprogesterone, the greater the release rate of progesterone. This exampledemonstrates that the release rate of a drug from the drug deliverydevice can be manipulated through the use of excipients, such ascellulosics.

Example 6 Release Kinetics of Estradiol and Progesterone from an EVAMatrix

EVA mixtures containing estradiol and progesterone were prepared asdescribed in Example 1 above, except that the EVA/drug mixtures were notfurther processed by injection molding or extrusion. Also, the EVA/drugmixtures were combined to form a double-sided disc, comprising estradiolon one side and progesterone on the other. After drying, the discs wereevaluated for their release kinetics. Briefly, Estradiol andprogesterone were placed in 100 ml of release media (70:30 PBS:EtOH,pH=6) at 37° C. on as rotary shaker (100 RPM). At the indicated timepoints, 100% of the media was collected for measurement and 100 ml ofrelease media was replaced. The media was measured by an Agilent 1100Series HPLC (Agilent). Estradiol and progesterone were detected by UV at230 nm. Results were calculated based on the area under the curvecompared to a 5 point calibration curve and depicted in FIG. 7 as thecumulative percent released. As shown in FIG. 7, estradiol andprogesterone have independent bi-phasic release kinetics.

Example 7 Intravaginal Administration of GnRH to Rhesus Monkeys

Polymeric mixtures comprising GnRH and a polyacrylic (polycarbophyl)based hydrogel, sold under the tradename Replens® (LDS ConsumerProducts, Cedar Rapids, Iowa), were prepared by mixing 10 mg of GnRHwith 2 g of hydrogel (0.5% wt/wt; pH 7). 2 g aliquots of theGnRH/hydrogel mixture were then placed in the vaginal tracts of fiveRhesus monkeys and allowed to remain there for 48 hours. Blood sampleswere taken at the specified intervals of time an assayed for GnRH and LHlevels.

Briefly, anti-GnRH was added to standard and test samples and incubatedat room temperature for 20-24 hours. The 1-125 labeled GnRH were dilutedto 21,000-22,5000 CPM/100 ul solutions and added to each tube of theassay and to total count tubes and incubated at room temperature for20-24 hours. 100 ul of sheep anti-rabbit gamma globulin (SARGG) and 100ul of 16% PEG (Fisher, Cat. # P156-500) was added to each tube andincubated at 4° C. for 1 hour. Samples were washed with 2 ml ofdistilled water and centrifuged at 3000 rpm for 20 minutes. Supernatantswere decanted and pellets were counted for one minute in a gammacounter. Results were expressed as ng/ml of GnRH and LH. FIG. 8 showsthe serum levels of GnRH (mean level in diamonds) in the monkeys as afunction of time, as well as the corresponding serum levels ofendogenous luteinizing hormone (LH) (mean level in squares).

This example demonstrates sufficient transvaginal absorption of GnRH toprovide ng/mL quantities of GnRH in the serum. As expected, the releaseof exogenous GnRH produces elevated levels of endogenous LH, thusdemonstrating the biological activity of the GnRH.

Example 8 Formation of a Multi-Linked Ring

The multi-linked intravaginal drug delivery device illustrated in FIG. 9can be prepared using poly(ethyl-co-vinyl acetate) (EVA) manufactured byAldrich Chemical Co. (Cat. No. 34,050-2; Lot No. 07322DR). 630(milligrams) mg of progesterone (Sigma Corp.; Cat. No. P-3972), and 3.0mg of estradiol (Sigma Corp.; Cat. no. E-1072) can be dissolvedseparately in approximately 5 mL of dichloromethane (Fluka Chem. Co.;Cat. No. 66740; Lot No. 404915/162800) in separate scintillation vials.Next, polymeric mixtures can be prepared by adding 1000 mg of EVA to theprogesterone solution and 300 mg of EVA to the estradiol solution, andmixing the EVA/drug compositions using a rotary shaker. Similarly, amixture comprising GnRH agonist (2.5 mg (D-Trp6-Pro9-Net-GnRH), 110 mgof methyl cellulose and 50 mg of EVA) can be prepared by dissolving themixture in 5 mL methylene chloride.

The resulting mixtures can then be individually solvent cast in dry iceusing ethanol as the solvent (Pharmco; Cat. No. 111 USP 200 CSGL; LotNo. M8241). The solvent can be evaporated overnight, and the dryEVA/drug mixtures can be ground into powders. The EVA/drug powders canbe placed in individual injection molding units (DSM, Geleen, Holland)and injected at 80° C. into the multiport molding of FIG. 9. Forexample, the Portal No. 1 can be injected with the mixture of GnRHagonist (2.5 mg GnRH agonist, 110 mg methyl cellulose and 50 mg EVA),the Portal No. 2 can be injected with the mixture of estradiol (3 mg ofestradiol and 300 mg of EVA), the Portal No. 3 can be injected with theprogesterone mix (630 mg of progesterone and 1 g of EVA) and the PortalNo. 4 can be injected with 500 mg of EVA (neat).

Example 9 Delayed Release Ring

The rate of hydration of the intravaginal device depends on manyfactors, including the rate of water penetration into the polymer. Therate of water penetration can be modulated by the osmotic pressurewithin the polymer. The osmotic pressure can be modulated by adding salt(NaCl, KCl, etc) to the formulation of the drug.

Estradiol and GnRH can be formulated as described herein. Yet,additional salt is added (300 mmol). These two drugs can form 2 segmentsof the ring and be designed to be release over 28 days (Table III). Athird segment can incorporate Progesterone without salt (Table IV).

TABLE III Drug Release from Drug Loading Circulation the Ring for 28days Drug Level per day of Release Estradiol   100 pg/Ml 100 μg   3 mgD-Trp6-Pro9- 10-100 pg/Ml 4 μg/Kg = 240 μg/day 6.8 mg Net-GnRH

TABLE IV Release from Drug Loading the Ring for 14 days Drug Circulationper day of Release Progesterone 6 ng/mL 45 mg 630 mg

As a result of the additional salt in the Estradiol and the GnRH agonistsegments, these drugs will rehydrate sooner and immediately start theirrelease which will continue over 28 days. However, the segmentcontaining progesterone will begin the release after 14 days andcontinue for 4 days. Thus, a single ring may be used as birth controlfor about one month with an early phase of 2 weeks with a zero orderrelease of just estradiol (“E2”) and GnRH agonist, followed by 14 daysof a zero order release of E2, GnRH agonist and progesterone.

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entireties. While thisinvention has been particularly shown and described with references topreferred embodiments thereof, it will be understood by those skilled inthe art that various changes in form and details may be made thereinwithout departing from the scope of the invention encompassed by theappended claims.

1. A method for relieving the symptoms associated with menopausal,perimenopausal and post-menopausal periods in a woman having saidperiods and in need of estrogen therapy, which method comprises: (a)providing a drug delivery device comprising a first segment and a secondsegment, wherein said first segment comprises a drug-permeable polymericsubstance and an estrogenic steroid; and (b) inserting into the vaginaof said woman the drug delivery device of step (a) to release aneffective amount of the estrogenic steroid to said woman.
 2. The methodof claim 1, wherein the estrogenic steroid is selected from the groupconsisting of a naturally occurring estrogen, a synthetic estrogen, anda selective estrogen receptor modulator.
 3. The method of claim 1,wherein the drug-permeable polymeric substance is a thermoplasticpolymer.
 4. The method of claim 2, wherein the thermoplastic polymer isan ethylene.
 5. The method of claim 1, wherein the drug delivery deviceis in the shape of a ring, a wafer, or a suppository.
 6. The method ofclaim 1, wherein the drug delivery device is in the shape of a ring. 7.A method for relieving the symptoms associated with the menopausal,perimenopausal and postmenopausal periods in a woman having said periodsand in need of estrogen therapy, which method comprises: (a) providing adrug delivery device comprising a first segment and a second segment,wherein said first segment comprises a drug-permeable polymericsubstance and a hormone replacement steroid; and (b) inserting into thevagina of said woman the drug delivery device of step (a) to release aneffective amount of the hormone replacement steroid to said woman. 8.The method of claim 7, wherein the hormone replacement steroid is anestrogenic steroid.
 9. The method of claim 8, wherein the estrogenicsteroid is selected from the group consisting of a naturally occurringestrogen, a synthetic estrogen, and a selective estrogen receptormodulator.
 10. The method of claim 8, wherein the estrogenic steroid isa member selected from the group consisting of estradiol, estradiolbenzoate, estradiol cypionate, estradiol dipropionate, estradiolenanthate, conjugated equine estrogen, estriol, estrone, estronesulfate, ethinyl estradiol, estrofurate, quinestrol and mestranol. 11.The method of claim 8, wherein the estrogenic steroid is selected fromthe group of selective estrogenic receptor modulators consisting oftamoxifen, raloxifene, clomiphene, droloxifene, idoxifene, toremifene,tibolone, ICI 182,780, ICI 164,384, diethylstilbesterol, genistein,nafoxidine, moxestrol, 19-nor-progesterone derivatives, and19-nor-testosterone derivatives.